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Fine particulate matter (PM 2.5) has been identified as a significant contributing factor to the exacerbation of chronic obstructive pulmonary disease (COPD). It has been observed that PM 2.5 may induce lung fibrosis in COPD, although the precise molecular mechanism behind this remains unclear. In a previous study, we demonstrated that PM 2.5 upregulates oxidative stress induced growth inhibitor 1 (OSGIN1), which in turn leads to injury in airway epithelial cells, thereby, suggesting a potential link between PM 2.5 exposure and COPD. Based on this, we hypothesized that OSGIN1 plays a role in PM 2.5 -induced fibrosis in COPD. Human bronchial epithelial cells (HBEs) were treated with cigarette smoke extract (CSE) to construct an in vitro model of COPD. Our findings revealed that PM 2.5 increased fibrosis indicators and upregulated OSGIN1 in CSE-stimulated HBEs (CSE-HBEs), and knockdown of OSGIN1 reduced the expression of fibrosis indicators. Through the use of microRNA target prediction software and the Gene Expression Omnibus database, we predicted miRNAs that targeted OSGIN1 in COPD. Subsequently, real-time polymerase chain reaction and western blot analysis confirmed that PM 2.5 modulated miR-654–5p to regulate OSGIN1 in CSE-HBEs. Western blot demonstrated that OSGIN1 induced autophagy, thereby exacerbating fibrosis in CSE-HBEs. In summary, our results suggest that PM 2.5 upregulates OSGIN1 through inhibiting miR-654–5p, leading to increased autophagy and fibrosis in CSE-HBEs. • PM 2.5 promotes fibrosis in CSE-HBEs. • PM 2.5 regulates OSGIN1 to modulate fibrosis in CSE-HBEs. • miR-654–5p negatively regulates OSGIN1 in PM 2.5 -treated CSE-HBEs. • OSGIN1 modulates autophagy in PM 2.5 -treated CSE-HBEs. [ABSTRACT FROM AUTHOR]

During recent decades, the metabolic dysfunction-associated steatohepatitis (MASH) field has witnessed several paradigm shifts, including the recognition of liver fibrosis as the main predictor of major adverse liver outcomes. Throughout this evolution, liver histology has been recognised as one of the main hurdles in MASH drug development due to its invasive nature, associated cost, and high inter- and intra-reader variability. Collective experience demonstrates the importance of consistency in the central reading process, where consensus methods have emerged as appropriate ways to mitigate against well-known challenges. Using crystalized knowledge in the field, stakeholders should collectively work towards the next paradigm shift, where non-invasive biomarkers will be considered surrogate endpoints for accelerated approval. In this review, we provide an overview of the evolution of the regulatory histology endpoints and the liver biopsy reading process, within the MASH trial landscape, over recent decades; we then review the biggest challenges associated with liver biopsy endpoints. Finally, we discuss and provide recommendations on the best practices for liver biopsy evaluation in MASH drug development. [ABSTRACT FROM AUTHOR]

• ECM synthesis poses significant demands for biomass generation with requirements different from cell proliferation. • With its high glycine and proline content, collagen synthesis imposes unique biosynthetic demands. • Pro-fibrotic signaling cascades mediate metabolic rewiring in activated fibroblasts. • Targeting the metabolic pathways supporting collagen synthesis provides opportunities for treating fibrotic conditions. • Nutrient availability influences metabolic pathways regulating collagen synthesis and creates new vulnerabilities. The extracellular matrix (ECM) is present in all tissues and crucial in maintaining normal tissue homeostasis and function. Defects in ECM synthesis and remodeling can lead to various diseases, while overproduction of ECM components can cause severe conditions like organ fibrosis and influence cancer progression and therapy resistance. Collagens are the most abundant core ECM proteins in physiological and pathological conditions and are predominantly synthesized by fibroblasts. Previous efforts to target aberrant collagen synthesis in fibroblasts by inhibiting pro-fibrotic signaling cascades have been ineffective. More recently, metabolic rewiring downstream of pro-fibrotic signaling has emerged as a critical regulator of collagen synthesis in fibroblasts. Here, we propose that targeting the metabolic pathways involved in ECM biomass generation provides a novel avenue for treating conditions characterized by excessive collagen accumulation. This review summarizes the unique metabolic challenges collagen synthesis imposes on fibroblasts and discusses how underlying metabolic networks could be exploited to create therapeutic opportunities in cancer and fibrotic disease. Finally, we provide a perspective on open questions in the field and how conceptual and technical advances will help address them to unlock novel metabolic vulnerabilities of collagen synthesis in fibroblasts and beyond. [ABSTRACT FROM AUTHOR]

Adverse left ventricular remodeling (ALVR) and subsequent heart failure after myocardial infarction (MI) remain a major cause of patient morbidity and mortality worldwide. Overt inflammation has been identified as the common pathway underlying myocardial fibrosis and development of ALVR post-MI. With its ability to simultaneously provide information about cardiac structure, function, perfusion, and tissue characteristics, cardiac magnetic resonance (CMR) is well poised to inform prognosis and guide early surveillance and therapeutics in high-risk cohorts. Further, established and evolving CMR-derived biomarkers may serve as clinical endpoints in prospective trials evaluating the efficacy of novel anti-inflammatory and antifibrotic therapies. This review provides an overview of post-MI ALVR and illustrates how CMR may help clinical adoption of novel therapies via mechanistic or prognostic imaging markers. [Display omitted] • HF secondary to MI remains a public health challenge. • As a clinical tool, CMR is the modality of choice in post-MI patients because it can reliably inform myocardial function and structure—including infarct size—and can be used for serial assessment of ALVR and risk stratification in patients post-MI. • As a translational tool with the unique ability of identifying myocardial inflammation and fibrosis, CMR has the potential for the following: 1) to offer insights in the mechanisms of action of novel therapies, beyond laboratory markers; and 2) to provide standardized imaging endpoints for treatment trials. • CMR is well poised to play a key role in accelerating the adoption of novel therapies from bench to bedside, paving the way for large-scale trials with hard clinical outcomes in the population of patients after MI. [ABSTRACT FROM AUTHOR]

Myocardial fibrosis (MF) forms part of the arrhythmic substrate for ventricular arrhythmias (VAs). This study sought to determine whether total myocardial fibrosis (TF) and gray zone fibrosis (GZF), assessed using cardiovascular magnetic resonance, are better than left ventricular ejection fraction (LVEF) in predicting ventricular arrhythmias in patients with nonischemic cardiomyopathy (NICM). Patients with NICM in a derivation cohort (n = 866) and a validation cohort (n = 848) underwent quantification of TF and GZF. The primary composite endpoint was sudden cardiac death or VAs (ventricular fibrillation or ventricular tachycardia). The primary endpoint was met by 52 of 866 (6.0%) patients in the derivation cohort (median follow-up: 7.5 years; Q1-Q3: 5.2-9.3 years). In competing-risks analyses, MF on visual assessment (MF VA) predicted the primary endpoint (HR: 5.83; 95% CI: 3.15-10.8). Quantified MF measures permitted categorization into 3 risk groups: a TF of >0 g and ≤10 g was associated with an intermediate risk (HR: 4.03; 95% CI: 1.99-8.16), and a TF of >10 g was associated with the highest risk (HR: 9.17; 95% CI: 4.64-18.1) compared to patients with no MF VA (lowest risk). Similar trends were observed in the validation cohort. Categorization into these 3 risk groups was achievable using TF or GZF in combination or in isolation. In contrast, LVEF of <35% was a poor predictor of the primary endpoint (validation cohort HR: 1.99; 95% CI: 0.99-4.01). MF VA is a strong predictor of sudden cardiac death and VAs in NICM. TF and GZF mass added incremental value to MF VA. In contrast, LVEF was a poor discriminator of arrhythmic risk. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fasciola hepatica extracellular vesicles (Hp EVs) induce extracellular matrix secretion. • Hp EVs reduce proliferation of hepatic stellate cells (HSCs) • Dicrocoelium dendriticum EVs (Dd EVs) trigger a global inflammatory response in HSCs and hepatocytes. • Dd EVs have a more potent anti-proliferative effect than Fh EVs. • Fh EVs are taken up faster and in higher amounts than Dd EVs by HSCs and hepatocytes. Fasciola hepatica and Dicrocoelium dendriticum are parasitic trematodes residing in the bile ducts of mammalian hosts, causing, in some cases, impairment of liver function and hepatic fibrosis. Previous studies have shown that extracellular vesicles released by F. hepatica (Fh EVs) and D. dendriticum (Dd EVs) induce a distinct phenotype in human macrophages, but there is limited information on the effect of parasitic EVs on liver cells, which interact directly with the worms in natural infections. In this study, we isolated Fh EVs and Dd EVs by size exclusion chromatography and labeled them with a lipophilic fluorescent dye to analyze their uptake by human hepatic stellate cells (HSC) and hepatocytes, important cell types in liver pathology, using synthetic liposomes as internal labeling and uptake control. We analyzed EV uptake and the proteome profiles after the treatment with EVs for both cell types. Our results reveal that EVs establish unique and specific interactions with stellate cells and hepatocytes, suggesting a different role of EVs derived from each parasite, depending on the migration route to reach their final niche. Fh EVs have a cytostatic effect on HSCs, but induce the extracellular matrix secretion and elicit anti-inflammatory responses in hepatocytes. Dd EVs have a more potent anti-proliferative effect than Fh EVs and trigger a global inflammatory response, increasing the levels of NF-κB and other inflammatory mediators in both cell types. These interactions may have a major influence on the progression of the disease, serving to generate conditions that may favor the establishment of the helminths in the host. [ABSTRACT FROM AUTHOR]

Prostaglandins have many roles in the equine reproductive tract, including but not limited to luteolysis, luteal support, ovulation, transport through the uterine tube, uterine contraction, embryonic mobility, inflammation, and fibrosis. Altered secretion of inflammatory proteins are likely to disrupt the balance of endometrial function and could impair fertility. Our overall goal was to measure the expression of several prostaglandin- and inflammation-related genes in mares with different degrees of endometrial histological changes. Our hypothesis was that mares with neutrophilic and lymphocytic plasmocytic inflammation, fibrosis, or different biopsy grades would have altered concentrations of prostaglandin E2 (PGE2) and F2α (PGF2α), as well as altered expression of inflammation- and prostaglandin-related genes, compared to mares with minimal to no histological changes on biopsy evaluation. Forty-five endometrial biopsies from estrous mares were assessed by a reproductive pathologist for the degree of neutrophilic inflammation, lymphocytic and plasmocytic inflammation, and fibrosis, and a biopsy grade was assigned based on the Kenney-Doig system. A low-volume uterine lavage was collected from a subset of twenty-six mares prior to biopsy collection and was used to measure PGE2 and PGF2α concentrations via ELISA. Total RNA was extracted from biopsies and mRNA expression was evaluated for twenty-five genes of interest. A restricted maximum likelihood linear model was used to compare differences of mRNA expression, with a statistical significance set at P < 0.05. There was no difference in the abundance of PGE2 or PGF2α between any of the variables tested. Mares with endometrial biopsy grade I had lower expression of NF-kB, PTGS1 and HPGD compared to grade IIA or IIB (P < 0.05). Mares with neutrophilic inflammation had decreased expression of NF-kB, PTGS1, PTGER4, CBR1, mPGES2 and PTGIS compared to mares without inflammation. Mares with mild or minimal endometrial fibrosis had increased expression of mPGES2 and PTGIS , compared to mares with moderate endometrial fibrosis. In conclusion, several genes were identified to be differentially expressed in mares with histological changes compared to mares with no to minimal histological changes. The presence of inflammation and fibrosis may alter the concentration of prostaglandins in endometrial tissue, which could impair many of the uterine reproductive and immune functions during estrus, affecting early embryo survival. • Prostaglandins were differentially expressed based on histological assessment. • Prostaglandin expression was increased in IIA and IIB endometrial biopsies. • mPGES2 and PTGIS relative expression were decreased with moderate fibrosis. • Endometrial biopsies with inflammation had decreased prostaglandin expression. [ABSTRACT FROM AUTHOR]

To elucidate the local microcirculation of the infrapatellar fat pad (IFP) in patients with knee osteoarthritis (KOA) by determining the changes in IFP hardness and hemoglobin concentration during isometric quadriceps exercise (IQE). In this observational cross-sectional study, patients diagnosed with bilateral KOA were included in the KOA group (30 knees), healthy older adults in the control group (20 knees), and younger adults in the young group (20 knees). Ultrasonography was performed at rest and during IQE to measure IFP hardness based on shear wave velocity. Near-infrared spectroscopy was performed to measure oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), and total hemoglobin (cHb) in the IFP before (Baseline), during (IQE task), and after IQE (Post). IFP hardness and O2Hb, HHb, and cHb concentration were analyzed using a linear mixed model for the groups and measurement points. During IQE, IFP hardness changes were significantly less in the KOA group than in the other groups (KOA: 95 % confidence intervals (CIs) [−0.854, 0.028]; control: 95 % CI [−0.941, −0.341]; and young: 95 % CI [−2.305, −1.706]). In the KOA group, O2Hb concentration exhibited no significant changes at Post compared with Baseline; however, significant changes were observed in the other groups (KOA: 95 % CI [−1.176, 0.423]; control: 95 % CI [−1.452, −0.276]; and young: 95 % CI [−4.062, −2.102]). During IQE, changes in hardness and hemoglobin concentration in the IFP were not significant in the KOA group, suggesting impaired local microcirculation of the IFP. [ABSTRACT FROM AUTHOR]

Synovial pathology has been linked to osteoarthritis (OA) pain in patients. Microscopic grading systems for synovial changes in human OA have been described, but a standardized approach for murine models of OA is needed. We sought to develop a reproducible approach and set of minimum recommendations for reporting of synovial histopathology in mouse models of OA. Coronal and sagittal sections from male mouse knee joints subjected to destabilization of medial meniscus (DMM) or partial meniscectomy (PMX) were collected as part of other studies. Stains included Hematoxylin and Eosin (H&E), Toluidine Blue (T-Blue), and Safranin O/Fast Green (Saf-O). Four blinded readers graded pathological features (hyperplasia, cellularity, and fibrosis) at specific anatomic locations. Inter-reader agreement of each feature score was determined. There was acceptable to very good agreement when using 3–4 individual readers. After DMM and PMX, expected medial predominant changes in hyperplasia and cellularity were observed, with fibrosis noted at 12 weeks post -PMX. Synovial changes were consistent from section to section in the mid-joint area. When comparing stains, H&E and T-blue resulted in better agreement compared to Saf-O stain. To account for the pathologic and anatomic variability in synovial pathology and allow for a more standardized evaluation that can be compared across studies, we recommend evaluating a minimum set of 3 pathological features at standardized anatomic areas. Further, we suggest reporting individual feature scores separately before relying on a single summed "synovitis" score. H&E or T-blue are preferred, inter-reader agreement for each feature should be considered. [ABSTRACT FROM AUTHOR]

Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases. While glycolytic shifts appear to be a key metabolic switch in activated stromal ECM-producing cells, several other cell types such as immune cells, whose functions are intricately connected to their metabolic characteristics, form a complex network of pro-fibrotic cellular crosstalk. This review purports to clarify shared and particular cellular responses and mechanisms across organs and etiologies. We discuss the impact of the cell-type specific metabolic reprogramming in fibrotic diseases in both experimental and human pathology settings, providing a rationale for new therapeutic interventions based on metabolism-targeted antifibrotic agents. [Display omitted] • Cell-type-specific metabolic alterations represent a major driver of organ fibrosis. • Defective mitochondrial function in parenchymal cells contributes to fibrogenesis. • Glycolysis is key for the activation of stromal extracellular matrix-producing cells. • Metabolism-targeting drugs have emerged as promising antifibrotic agents. [ABSTRACT FROM AUTHOR]

After burn injury there is considerable variation in scar outcome, partially due to genetic factors. Scar vascularity is one characteristic that varies between individuals, and this study aimed to identify genetic variants contributing to different scar vascularity outcomes. An exome-wide array association study and gene pathway analysis was performed on a prospective cohort of 665 patients of European ancestry treated for burn injury, using their scar vascularity (SV) sub-score, part of the modified Vancouver Scar Scale (mVSS), as an outcome measure. DNA was genotyped using the Infinium HumanCoreExome-24 BeadChip, imputed to the Haplotype Reference Consortium panel. Associations between genetic variants (single nucleotide polymorphisms) and SV were estimated using an additive genetic model adjusting for sex, age, % total body surface area and number of surgical procedures, utilising linear and multinomial logistic regression. No individual genetic variants achieved the cut-off threshold for significance. Gene sets were also analysed using the Functional Mapping and Annotation (FUMA) platform, in which biological processes indirectly related to angiogenesis were significantly represented. This study suggests that SNPs in genes associated with angiogenesis may influence SV, but further studies with larger datasets are essential to validate these findings. [Display omitted] • 665 burn patients genotyped and imputed for an association study. • Associations made between gene variants and scar vascularity. • No individual genetic variants reached significance due to sample size. • Gene set analysis found 8 gene significant sets, some involved in angiogenesis. • Largest association study on burn cohort to date. [ABSTRACT FROM AUTHOR]

LUZP1 expression was increased in pressure overload-induced cardiac hypertrophy in postnatal mice. By constructing cardiac-specific Luzp1 knockout and transgenic mice, we demonstrated that cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated pressure overload-induced cardiac hypertrophy and dysfunction. Mechanistically, LUZP1 elevated SHP1 expression to inactivate Stat3 pathway, thereby preventing pathological cardiac hypertrophy. Accordingly, SHP1 silence blocked the anti-hypertrophic effects of LUZP1 in vivo and in vitro. [Display omitted] • LUZP1 expression was progressively increased in hearts after TAC surgery. • Cardiac-specific LUZP1 deficiency aggravated pressure overload-induced cardiac hypertrophy. • Cardiac-specific LUZP1 overexpression attenuated pressure overload-induced cardiac hypertrophy. • Stat3 pathway was a downstream target of LUZP1 in regulating pathological cardiac hypertrophy. • LUZP1 elevated SHP1 expression to inactivate Stat3 pathway. Cardiac hypertrophy is an important contributor of heart failure, and the mechanisms remain unclear. Leucine zipper protein 1 (LUZP1) is essential for the development and function of cardiovascular system; however, its role in cardiac hypertrophy is elusive. This study aims to investigate the molecular basis of LUZP1 in cardiac hypertrophy and to provide a rational therapeutic approach. Cardiac-specific Luzp1 knockout (cKO) and transgenic mice were established, and transverse aortic constriction (TAC) was used to induce pressure overload-induced cardiac hypertrophy. The possible molecular basis of LUZP1 in regulating cardiac hypertrophy was determined by transcriptome analysis. Neonatal rat cardiomyocytes were cultured to elucidate the role and mechanism of LUZP1 in vitro. LUZP1 expression was progressively increased in hypertrophic hearts after TAC surgery. Gain- and loss-of-function methods revealed that cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated pressure overload-elicited hypertrophic growth and cardiac dysfunction in vivo and in vitro. Mechanistically, the transcriptome data identified Stat3 pathway as a key downstream target of LUZP1 in regulating pathological cardiac hypertrophy. Cardiac-specific Stat3 deletion abolished the pro-hypertrophic role in LUZP1 cKO mice after TAC surgery. Further findings suggested that LUZP1 elevated the expression of Src homology region 2 domain-containing phosphatase 1 (SHP1) to inactivate Stat3 pathway, and SHP1 silence blocked the anti-hypertrophic effects of LUZP1 in vivo and in vitro. We demonstrate that LUZP1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling, and targeting LUZP1 may develop novel approaches to treat pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Equine endometrosis is a degenerative and predominantly fibrotic condition resulting from progressive and irreversible multifactorial causes that influence the endometrium of mare. Tissue remodeling in the equine endometrium occurs as part of the pathogenesis of endometrosis, a process characterized by a shift in extracellular matrix (ECM) components. The relationship between matrix metalloproteinases and their specific inhibitors is crucial for the remodeling process. Collagen play a significant role in maintaining a healthy uterus and may promote fibrotic processes. The aim of this study was to quantify endometrial collagen deposition using picrosirius 25 red (PSR) staining, and to evaluate gene expression of collagen type 2 (COL-2) and 3 (COL-3), matrix metalloproteinases 1 (MMP-1) and 2 (MMP-2), their tissue inhibitor (TIMP-2), and tumor necrosis factor (TNF-α) in the endometrium of mares with different grades of fibrosis. The samples (n = 34) were classified into three categories based on the frequency and distribution of fibrosis-related changes in the endometrium: Category I (healthy endometrium, n = 12), Category II (moderate fibrosis, n = 12), and Category III (severe fibrosis, n = 10). Collagen quantification demonstrate a substantial proportional increase (P < 0.0001) in collagen deposition across Category I (11.72 ± 1.39 %), Category II (17.76 ± 1.29 %), and Category III (24.15 ± 1.87 %). In transcript evaluations, higher COL-2 expression was found in Category II than in mares classified as Category I or III. MMP-1 showed increased transcript expression in Category II compared to Category III endometrial samples. Higher expression of MMP-2 was detected in Category III than in Category I and II. TIMP-2 showed lower mRNA expression in Category III vs Category I and II. However, TNF-α gene expression was higher in Category II than in Categories I and III. This study demonstrates that endometrial evaluation using PSR can play an important role in routine analyses for the detection and objective quantification of collagen in endometrial tissues. Additionally, this study demonstrated through gene expression analysis that MMP-1 may be linked to physiological endometrial remodeling. In contrast, MMP-2 could be associated with fibrogenesis in the endometrium, which is regulated by the inhibitor TIMP-2. Furthermore, COL-2 and TNF-α could be considered as biological markers involved in the progression endometrosis in mares. As such, the results of this study may contribute to the development of future antifibrotic therapies that aim to delay or even reverse the pathological remodeling of the extracellular matrix in the uterus, in addition to optimizing the diagnosis and prognosis of endometrial fibrosis in mares. • Increased collagen accumulation in the uterine of mares with endometrosis. • Positive correlation between the animals' age and uterine collagen deposition. • Lower MMP-2 and higher TIMP-2 expression could be key for ECM reorganization. • TNF-α and COL-2 as possible markers of developing endometrosis. [ABSTRACT FROM AUTHOR]

La fasciite à éosinophiles (FE), ou maladie de Shulman, est une pathologie rare du tissu conjonctif caractérisée par un œdème et une induration douloureuse des membres et du tronc, souvent associés à une hyperéosinophilie et une hypergammaglobulinémie. Elle provoque des arthralgies et une limitation des amplitudes articulaires induisant un important retentissement fonctionnel et une altération de la qualité de vie. Depuis sa description par Shulman en 1974, plus de 300 cas ont été rapportés. Nous présentons ici une revue des actualités diagnostiques, physiopathologiques, et thérapeutiques de cette maladie. L'imagerie par résonance magnétique est utile pour orienter le diagnostic et la biopsie. Le diagnostic repose sur la biopsie cutanée profonde comportant le fascia qui met en évidence un œdème, une scléro-fibrose du fascia musculaire et du tissu sous-cutané et un infiltrat inflammatoire parfois composé de polynucléaires éosinophiles. Des formes secondaires à l'utilisation des inhibiteurs de checkpoint ont été décrites et l'apparition d'une sclérose cutanée chez ces patients doit faire évoquer le diagnostic. La physiopathologie reste mal connue et la prise en charge mal codifiée, reposant sur des données issues de cohorte rétrospectives et cas cliniques. Le traitement de première intention consiste en corticothérapie orale, parfois associée à un immunosuppresseur, en premier lieu le méthotrexate. Une meilleure compréhension de la physiopathologie permet d'envisager de nouvelles perspectives thérapeutiques et de préciser la place de thérapies ciblées telles que les inhibiteurs de l'interleukine 5 (IL-5) et de l'IL-6. Eosinophilic fasciitis (EF) is a rare connective tissue disorder characterized by painful edema and induration of the limbs and trunk, likely associated with hypereosinophilia and hypergammaglobulinemia. EF causes arthralgia and range of motion limitation, leading to significant functional impairment and poor quality of life. Since its description by Shulman in 1974, over 300 cases have been reported. We present here a review of the latest diagnostic, pathophysiological and therapeutic developments in this disease. Magnetic resonance imaging appears useful to guide diagnosis and biopsy. Diagnosis is based on a deep skin biopsy involving the fascia, which will reveal edema, sclerofibrosis of the muscular fascia and subcutaneous tissue, and an inflammatory infiltrate sometimes composed of eosinophilic polynuclear cells. EF may occur in patients treated with immune checkpoint inhibitors and the diagnosis should be raised in case of cutaneous sclerosis in these patients. The pathophysiology of the disease remains poorly understood, and its management lacks randomized, controlled, blinded trials. First-line treatment consists in oral corticosteroid therapy, sometimes combined with an immunosuppressant, mainly methotrexate. A better understanding of the pathophysiology has opened new therapeutic perspectives and clarified the role of targeted therapies in the management of EF, such as interleukin-6 inhibitors, whose efficacy has been reported in several cases. [ABSTRACT FROM AUTHOR]

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The aim of this study was to determine whether liver fibrosis is associated with heart failure in a general population cohort, and if genetic polymorphisms (PNPLA3 rs738409; TM6SF2 rs58542926), linked to increased risk of liver fibrosis and decreased risk of coronary artery disease, modify this association. Using UK Biobank data, we prospectively examined the relationship between noninvasive fibrosis markers (nonalcoholic fatty liver disease [NAFLD] fibrosis score [NFS], Fibrosis-4 [FIB-4] and aspartate transaminase [AST] to platelet ratio index [APRI]) and incident hospitalization/death from heart failure (n = 413,860). Cox-regression estimated hazard ratios (HRs) for incident heart failure. Effects of PNPLA3 and TM6SF2 on the association between liver fibrosis and heart failure were estimated by stratifying for genotype and testing for an interaction between genotype and liver fibrosis using a likelihood ratio test. A total of 12,527 incident cases of heart failure occurred over a median of 10.7 years. Liver fibrosis was associated with an increased risk of hospitalization or death from heart failure (multivariable adjusted high-risk NFS score HR, 1.59; 95% confidence interval [CI],1.47-1.76; P <.0001; FIB-4 HR, 1.69; 95% CI, 1.55-1.84; P <.0001; APRI HR, 1.85; 95% CI, 1.56-2.19; P <.0001; combined fibrosis scores HR, 1.90; 95% CI, 1.44-2.49; P <.0001). These associations persisted for people with metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD with alcohol consumption (Met-ALD), and harmful alcohol consumption. PNPLA3 rs738409 GG and TM6SF2 rs58542926 TT did not attenuate the positive association between fibrosis markers and heart failure. For PNPLA3 , a statistically significant interaction was found between PNPLA3 rs738409, FIB-4, APRI score, and heart failure. In the general population, serum markers of liver fibrosis are associated with increased hospitalization/death from heart failure. Genetic polymorphisms associated with liver fibrosis were not positively associated with elevated heart failure risk. [Display omitted] [ABSTRACT FROM AUTHOR]

Progranulin (PGRN), a multifunctional growth factor-like protein expressed by a variety of cell types, serves an important function in the physiologic and pathologic processes of fibrotic diseases, including wound healing and the inflammatory response. PGRN was discovered to inhibit pro-inflammation effect by competing with tumor necrosis factor-alpha (TNF- α) binding to TNF receptors. Notably, excessive tissue repair in the development of inflammation causes tissue fibrosis. Previous investigations have indicated the significance of PGRN in regulating inflammatory responses. Recently, multiple studies have shown that PGRN was linked to fibrogenesis, and was considered to monitor the formation of fibrosis in multiple organs, including liver, cardiovascular, lung and skin. This paper is a comprehensive review summarizing our current knowledge of PGRN, from its discovery to the role in fibrosis. This is followed by an in-depth look at the characteristics of PGRN, consisting of its structure, basic function and intracellular signaling. Finally, we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis. Progranulin (PGRN) is a promising biomarker and therapeutic target for fibrotic diseases. PGRN can act both as a pro-fibrotic and as anti-fibrotic factor in several fibrotic diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease globally. It initiates with simple steatosis (NAFL) and can progress to the more severe condition of non-alcoholic steatohepatitis (NASH). NASH often advances to end-stage liver diseases such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Notably, the transition from NASH to end-stage liver diseases is irreversible, and the precise mechanisms driving this progression are not yet fully understood. Consequently, there is a critical need for the development of effective therapies to arrest or reverse this progression. This review provides a comprehensive overview of the pathogenesis of NASH, examines the current therapeutic targets and pharmacological treatments, and offers insights for future drug discovery and development strategies for NASH therapy. [ABSTRACT FROM AUTHOR]

Damage to the heart can start the repair process and cause cardiac remodeling. B cells play an important role in this process. B cells are recruited to the injured place and activate cardiac remodeling through secreting antibodies and cytokines. Different types of B cells showed specific functions in the heart. Among all types of B cells, heart-associated B cells play a vital role in the heart by secreting TGFβ1. B cells participate in the activation of fibroblasts and promote cardiac fibrosis. Four subtypes of B cells in the heart revealed the relationship between the B cells' heterogeneity and cardiac remodeling. Many cardiovascular diseases like atherosclerosis, heart failure (HF), hypertension, myocardial infarction (MI), and dilated cardiomyopathy (DCM) are related to B cells. The primary mechanisms of these B cell-related activities will be discussed in this review, which may also suggest potential novel therapeutic targets. • We summarized the relationship between B cells and cardiac remodeling. • In different cardiovascular diseases, B cells express different biomarkers and play different roles in cardiac fibrosis. • According to the mechanism of B cell action, potential therapeutic targets were proposed. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a major risk factor for atrial structural remodeling and atrial fibrillation (AF). Calpain activity is hypothesized to promote atrial remodeling and AF. The purpose of this study was to investigate the role of calpain in diabetes-associated AF, fibrosis, and calcium handling dysfunction. DM-associated AF was induced in wild-type (WT) mice and in mice overexpressing the calpain inhibitor calpastatin (CAST-OE) using high-fat diet feeding followed by low-dose streptozotocin injection (75 mg/kg). DM and AF outcomes were assessed by measuring blood glucose levels, fibrosis, and AF susceptibility during transesophageal atrial pacing. Intracellular Ca2+ transients, spontaneous Ca2+ release events, and intracellular T-tubule membranes were measured by in situ confocal microscopy. WT mice with DM had significant hyperglycemia, atrial fibrosis, and AF susceptibility with increased atrial myocyte calpain activity and Ca2+ handling dysfunction relative to control treated animals. CAST-OE mice with DM had a similar level of hyperglycemia as diabetic WT littermates but lacked significant atrial fibrosis and AF susceptibility. DM-induced atrial calpain activity and downregulation of the calpain substrate junctophilin-2 were prevented by CAST-OE. Atrial myocytes of diabetic CAST-OE mice exhibited improved T-tubule membrane organization, Ca2+ handling, and reduced spontaneous Ca2+ release events compared to littermate controls. This study confirmed that DM promotes calpain activation, atrial fibrosis, and AF in mice. CAST-OE effectively inhibits DM-induced calpain activation and reduces atrial remodeling and AF incidence through improved intracellular Ca2+ homeostasis. Our results support calpain inhibition as a potential therapy for preventing and treating AF in DM patients. [ABSTRACT FROM AUTHOR]

The PNPLA3 rs738409 C>G (encoding for I148M) variant is a risk locus for the fibrogenic progression of chronic liver diseases, a process driven by hepatic stellate cells (HSCs). We investigated how the PNPLA3 I148M variant affects HSC biology using transcriptomic data and validated findings in 3D-culture models. RNA sequencing was performed on 2D-cultured primary human HSCs and liver biopsies of individuals with obesity, genotyped for the PNPLA3 I148M variant. Data were validated in wild-type (WT) or PNPLA3 I148M variant-carrying HSCs cultured on 3D extracellular matrix (ECM) scaffolds from human healthy and cirrhotic livers, with/without TGFB1 or cytosporone B (Csn-B) treatment. Transcriptomic analyses of liver biopsies and HSCs highlighted shared PNPLA3 I148M-driven dysregulated pathways related to mitochondrial function, antioxidant response, ECM remodelling and TGFB1 signalling. Analogous pathways were dysregulated in WT/PNPLA3-I148M HSCs cultured in 3D liver scaffolds. Mitochondrial dysfunction in PNPLA3-I148M cells was linked to respiratory chain complex IV insufficiency. Antioxidant capacity was lower in PNPLA3-I148M HSCs, while reactive oxygen species secretion was increased in PNPLA3-I148M HSCs and higher in bioengineered cirrhotic vs. healthy scaffolds. TGFB1 signalling followed the same trend. In PNPLA3-I148M cells, expression and activation of the endogenous TGFB1 inhibitor NR4A1 were decreased: treatment with the Csn-B agonist increased total NR4A1 in HSCs cultured in healthy but not in cirrhotic 3D scaffolds. NR4A1 regulation by TGFB1/Csn-B was linked to Akt signalling in PNPLA3-WT HSCs and to Erk signalling in PNPLA3-I148M HSCs. HSCs carrying the PNPLA3 I148M variant have impaired mitochondrial function, antioxidant responses, and increased TGFB1 signalling, which dampens antifibrotic NR4A1 activity. These features are exacerbated by cirrhotic ECM, highlighting the dual impact of the PNPLA3 I148M variant and the fibrotic microenvironment in progressive chronic liver diseases. Hepatic stellate cells (HSCs) play a key role in the fibrogenic process associated with chronic liver disease. The PNPLA3 genetic mutation has been linked with increased risk of fibrogenesis, but its role in HSCs requires further investigation. Here, by using comparative transcriptomics and a novel 3D in vitro model, we demonstrate the impact of the PNPLA3 genetic mutation on primary human HSCs' behaviour, and we show that it affects the cell's mitochondrial function and antioxidant response, as well as the antifibrotic gene NR4A1. Our publicly available transcriptomic data, 3D platform and our findings on NR4A1 could facilitate the discovery of targets to develop more effective treatments for chronic liver diseases. [Display omitted] • Transcriptomic analyses were performed to investigate the involvement of the PNPLA3 I148M variant in the pro-fibrogenic features of HSCs. • HSCs carrying the PNPLA3 I148M variant are characterized by mitochondrial dysfunction and decreased antioxidant capacity. • HSCs carrying the PNPLA3 I148M variant have increased TGFB1 signalling which reduces the antifibrotic activity of its endogenous inhibitor NR4A1. • The ECM of cirrhotic liver further exacerbates the effects of the PNPLA3 I148M variant on HSC behaviour. [ABSTRACT FROM AUTHOR]

Continuous and aberrant activation of myofibroblasts is the hallmark of pathological fibrosis (e.g., abnormal wound healing). The deposition of excessive extracellular matrix (ECM) components alters or increases the stiffness of tissue and primarily accounts for multiple organ dysfunctions. Among various proteins, Cadherin-11 (CDH11) has been reported to be overexpressed on myofibroblasts in fibrotic tissues. Anti-apoptotic proteins such as (B cell lymphoma-2) (BCL-2) are also upregulated on myofibroblasts. Therefore, we hypothesize that CDH11 could be a targeted domain for cell-specific drug delivery and targeted inhibition of BCL-2 to ameliorate the development of fibrosis in the skin. To prove our hypothesis, we have developed liposomes (LPS) conjugated with CDH11 neutralizing antibody (antiCDH11) to target cell surface CDH11 and loaded these LPS with a BCL-2 inhibitor, Navitoclax (NAVI), to induce apoptosis of CDH11 expressing fibroblasts. The developed LPS were evaluated for physicochemical characterization, stability, in vitro therapeutic efficacy using dermal fibroblasts, and in vivo therapeutic efficacy in bleomycin-induced skin fibrosis model in mice. The findings from in vitro and in vivo studies confirmed that selectivity of LPS was improved towards CDH11 expressing myofibroblasts, thereby improving therapeutic efficacy with no indication of adverse effects. Hence, this novel research work represents a versatile LPS strategy that exhibits promising potential for treating skin fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases. [ABSTRACT FROM AUTHOR]

Steatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD. Individuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below −1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria. A total of 1410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34–0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00–1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97–1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD. The present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine. [ABSTRACT FROM AUTHOR]

Current treatments of eosinophilic esophagitis (EoE) aim to eliminate esophageal mucosal inflammation and attenuate, stabilize, or reverse stricture formation. However, our ability to study the long-term course of esophageal strictures in patients with EoE is hampered by the short-term existence of this disease. It is unclear to what degree of control of inflammation is needed to prevent stricture formation. Additionally, identified phenotypes of EoE may ultimately dictate different levels of concern and time intervals for developing fibrosis. Currently, multiple methods are used to monitor patients' disease progression to fibrosis, as symptoms alone do not correlate with disease activity. Endoscopic findings and mucosal histology are used to monitor disease activity, but these focus on improvements in inflammation with inconsistent evaluation of underlying fibrosis. The use of functional lumen impedance planimetry, barium esophagraphy, and endoscopic ultrasound continues to expand in EoE. The rapid advancements in EoE have led to an armamentarium of measuring tools and therapies that holistically characterize disease severity and response to therapy. Nevertheless, our ability to evaluate gross esophageal fibrosis and stricture formation from a transmural rather than mucosal view should be a focus of future investigations because it is essential to monitoring and modulating the trajectory of EoE. [ABSTRACT FROM AUTHOR]

The worldwide accepted repair for indirect inguinal hernia in children is high ligation of the hernia sac with open herniotomy. However, laparoscopic pediatric inguinal hernia repair (IHR) has been gaining popularity in the last two decades. An experimental study was conducted to investigate the effects of different intraperitoneal IHR suture techniques on the collagen formation at the hernia sac neck. Present study was conducted on thirty-five male adult (3–6 months old) Wistar-Albino rats (260–300 g). Intraperitoneal IHR with different hernia sac neck suturing techniques (purse string suture only, transfixation suture only and purse string suture plus transfixation suture) were performed through median laparotomy using open operative techniques. Non-absorbable 2/0 braided polyester suture with 16 mm 1/2 curved round needle (Ti-cron, Covidien, MN) was used as suture material. The highest collagen thickness around the suture was detected in intraperitoneal IHR with purse-string plus transfixation suture group. The collagen thickness of the intraperitoneal IHR with purse string suture only and IHR with tranfixation suture only groups were not statistically significantly different. The collagen thickness of the intraperitoneal IHR with purse string suture plus transfixation suture group was statistically significantly higher compared with the intraperitoneal IHR with purse string suture only and intraperitoneal IHR with transfixation suture only groups. The combined usage of purse string suture and transfixation suture during laparoscopic intraperitoneal inguinal hernia repair further stimulates mesothelial fibrosis at the hernia sac neck compared with mesothelial fibrosis induced by purse string suture only or transfixation suture only. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

The identification of the pulmonary veins as a trigger source for atrial fibrillation (AF) has established pulmonary vein isolation (PVI) as a key target for AF ablation. However, PVI alone does not prevent recurrent AF in many patients, and numerous additional ablation strategies have failed to improve on PVI outcomes. This therapeutic limitation may be due, in part, to a failure to identify and intervene specifically on the pro-fibrillatory substrate within the atria and pulmonary veins. In this review paper, we highlight several emerging approaches with clinical potential that target atrial cardiomyopathy—the underlying anatomic, electrical, and/or autonomic disease affecting the atrium—in various stages of practice and investigation. In particular, we consider the evolving roles of risk factor modification, targeting of epicardial adipose tissue, tissue fibrosis, oxidative stress, and the inflammasome, along with aggressive early anti-AF therapy in AF management. Attention to combatting substrate development promises to improve outcomes in AF. [Display omitted] • As a therapeutic target for AF, atrial cardiomyopathy is not addressed by ablation. • Biological and clinical data identify adjunctive approaches to AF management that can improve outcomes. • Further studies personalizing therapy to individual causative factors and mechanistic mediators are needed. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading etiology of chronic liver disease worldwide, with increasing incidence and prevalence in the setting of the obesity epidemic. MASH is also a leading indication for liver transplantation, given its associated risk of progression to end-stage liver disease. A key challenge in managing MASH is the lack of approved pharmacotherapy. In its absence, lifestyle interventions with a focus on healthy nutrition and regular physical activity have been the cornerstone of therapy. Real-world efficacy and sustainability of lifestyle interventions are low, however. Pharmacotherapy development for MASH is emerging with promising data from several agents with different mechanisms of action (MOAs) in phase 3 clinical trials. In this review, we highlight ongoing challenges and potential solutions in drug development for MASH and provide an overview of available data from emerging therapies across multiple MOAs. Metabolic dysfunction-associated steatohepatitis (MASH) is a leading etiology of chronic liver disease worldwide. In this review, Tincopa et al. highlight challenges and potential solutions in drug development for MASH. They cover current advances in pharmacotherapy for MASH, presenting promising data from several agents in the pipeline. [ABSTRACT FROM AUTHOR]

To identify the anti-fibrosis effect of PRAS40 in scar, and its potential mechanism. We constructed a rat model of hypertrophic scarthat was locally injected the PRAS40 overexpression adenoviruses, mTORC1 inhibitor MHY1485 and activator rapamycin, and further observed the pathological changes of skin tissue and the severity of fibrosis by HE, Masson and sirius red staining, and analyzed the deposition of a-SMA and collagen I by western blot and immunofluorescence test. Meanwhile, the co-localization of KLF4 with a-SMA and type I collagen was analyzed, as well as the regulatory effect of PRAS40 on KLF4. In addition, we also verified whether the inhibition of scar fibrosis by PRAS40 is related to mTORC1, and whether the upregulation of KLF4 is related to mTORC1. The results showed that the expression of PRAS40 was low and p-PRAS40 was high in scar skin tissue. After local injection of PRAS40 overexpression adenovirus, the expression of PRAS40 in skin tissue was increased. The overexpression of PRAS40 can inhibit scar skin fibrosis and reduce the content of a-SMA and collagen I. Further mechanism analysis confirms that the inhibitory effect of PRAS40 on skin fibrosis is related to mTORC1, and PRAS40 inhibits the activation of mTORC1. The expression of KLF4 is relatively low in scar tissue. PRAS40 administration upregulated the expression of KLF4, which is related to mTORC1 PRAS40 significantly improves fibrosis of scar skin tissue and increases the expression of KLF4 in scars. The anti-fibrotic effect of PRAS40 depends on mTORC1. • Exogenous PRAS40 improved the scar fibrosis in the injured tissues of HS rats. • mTORC1 activation accelerates fibrosis degree in the injured skin. PRAS40 is also an inhibitor of mTORC1 inactivation, so we believe that the effect of PRAS40 on scar fibrosis is related to mTORC1. • KLF4 is an important regulator in the development of fibrosis. • Consistent with the previous report, we found a high expression of KLF4 in skin tissues , while after HS modeling, KLF4 was downregulated. Interestingly, PRAS40 could modulate the KLF4 expression, and this effect was also related to mTORC1. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is characterized by a densely fibrotic stroma. The fibrotic stroma hinders the intratumoral penetration of nanomedicine and diminishes therapeutic efficacy. Fibrosis is characterized by an abnormal organization of extracellular matrix (ECM) components, namely the abnormal deposition and/or orientation of collagen and fibronectin. Abnormal ECM organization is chiefly driven by pathological signaling in pancreatic stellate cells (PSCs), the main cell type involved in fibrogenesis. However, whether targeting signaling pathways involved in abnormal ECM organization improves the intratumoral penetration of nanomedicines is unknown. Here, we show that targeting transforming growth factor-β (TGFβ)/Rho-associated kinase (ROCK) 1/2 signaling in PSCs normalizes ECM organization and concomitantly improves macromolecular permeability of the fibrotic stroma. Using a 3-dimensional cell culture model of the fibrotic pancreatic cancer microenvironment, we found that pharmacological inhibition of TGFβ or ROCK1/2 improves the permeation of various macromolecules. By using an isoform-specific pharmacological inhibitor and siRNAs, we show that targeting ROCK2, but not ROCK1, alone is sufficient to normalize ECM organization and improve macromolecular permeability. Moreover, we found that ROCK2 inhibition/knockdown attenuates Yes-associated protein (YAP) nuclear localization in fibroblasts co-cultured with pancreatic cancer cells in 3D. Finally, pharmacological inhibition or siRNA-mediated knockdown of YAP normalized ECM organization and improved macromolecular permeability. Our results together suggest that the TGFβ/ROCK2/YAP signaling axis may be therapeutically targeted to normalize ECM organization and improve macromolecular permeability to augment therapeutic efficacy of nanomedicines in pancreatic cancer. [Display omitted] • Fibrosis is a hallmark of pancreatic cancer and impedes intratumoral drug delivery. • Pancreatic stellate cells (PSCs) abnormally remodel the extracellular matrix (ECM). • Macromolecular delivery through fibrotic tissue assessed in a 3D in vitro model. • Targeting TGFβ/ROCK/YAP in PSCs attenuated ECM remodeling and improved delivery. • Targeting ROCK2, rather than ROCK1, was more effective. [ABSTRACT FROM AUTHOR]

• Disorganized smooth muscle, fibrosis and fewer endometrial glands are characteristics of uterine scars. • Glandular structure could be responsible for healing defects after caesarean section. • Uterine scar defects have a fibroblastic highly collagenic stromal reaction. • No correlation was found between biomechanical characteristics and histology. The rate of caesarean section (CS) is increasing worldwide. Defects in uterine healing have a major gynaecological and obstetric impact (uterine rupture, caesarean scar defect, caesarean scar pregnancy, placenta accreta spectrum). The complex process of cellular uterine healing after surgery, and specifically after CS, remains poorly understood in contrast to skin wound healing. This literature review on uterine wound healing was mainly based on histological observations, particularly after CS. The primary objective of the review was to examine the effects of CS on uterine tissue at the cellular level, based on histological observations. The secondary objectives were to describe the biomechanical characteristics and the therapies used to improve scar tissue after CS. This review was performed using PRISMA criteria, and PubMed was the data source. The study included all clinical and animal model studies with CS and histological analysis of the uterine scar area (macroscopic, microscopic, immunohistochemical and biomechanical). Twenty studies were included: 10 human and 10 animal models. In total, 533 female humans and 511 female animals were included. Review articles, meeting abstracts, case series, case reports, and abstracts without access to full-text were excluded. The search was limited to studies published in English. No correlation was found between cutaneous and uterine healing. The histology of uterine scars is characterized by disorganized smooth muscle, fibrosis with collagen fibres and fewer endometrial glands. As for skin healing, the initial inflammation phase and mediation of some growth factors (particularly connective tissue growth factor, vascular endothelial growth factor, platelet-derived growth factor, tumour necrosis factor α and tumour necrosis factor β) seem to be essential. This initial phase has an impact on the subsequent phases of proliferation and maturation. Collagen appears to play a key role in the initial granulation tissue to replace the loss of substance. Subsequent maturation of the scar tissue is essential, with a decrease in collagen and smooth muscle restoration. Unlike skin, the glandular structure of uterine tissue could be responsible for the relatively high incidence of healing defects. Uterine scar defects after CS are characterized by an atrophic disorganized endometrium with atypia and a fibroblastic highly collagenic stromal reaction. Concerning immunohistochemistry, one study found a decrease in tumour necrosis factor β in uterine scar defects. No correlation was found between biomechanical characteristics (particularly uterine strength) and the presence of a collagenous scar after CS. Based on the findings of this review, an illustration of current understanding about uterine healing is provided. There is currently no validated prevention of caesarean scar defects. Various treatments to improve uterine healing after CS have been tested, and appeared to have good efficacy in animal studies: alpha lipoic acid, growth factors, collagen scaffolds and mesenchymal stem cells. Further prospective studies are needed. [ABSTRACT FROM AUTHOR]

To estimate the number of patients who required a referral to hepatologists following the 2016 EASL–EASD–EASO guideline and a second-line vibration controlled transient elastography (VCTE) examination following the 2021 EASL guideline according to obesity, glycated hemoglobin (HbA1c), blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) control status in patients with type 2 diabetes mellitus (T2DM). A total of 2515 T2DM patients who were hospitalized were cross-sectionally assessed. When we applied the 2016 EASL–EASD–EASO guideline, 26.8 %–46.4 % (depending on the scores used for diagnosing fibrosis) of T2DM patients needed a referral to hepatologists. When we applied the 2021 EASL guideline, a VCTE examination was required in 10.9 %–35 % (depending on the scores used for diagnosing fibrosis) of T2DM patients. The referral rates and the VCTE requirement were even higher in patients who were obese and/or had poor HbA1c, BP, and/or LDL-C control. Application of the screening guidelines would lead to a referral to hepatologists or a second-line VCTE examination requirement for a substantial number of T2DM patients, regardless of obesity and metabolic goal attainment status. • A great number of diabetic patients needed a referral to hepatologists. • A great number of diabetic patients require a second-line VCTE examination. • A great number of diabetic patients needed a referral to hepatologists regardless of obeisty status. • A great number of diabetic patients needed a referral to hepatologists regardless of care goal attainment status. [ABSTRACT FROM AUTHOR]

Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist with favorable effects on fatty and glucose metabolism, has been considered the leading candidate drug for nonalcoholic steatohepatitis (NASH) treatment. However, its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major drawback. Ferroptosis, a newly recognized form of cell death characterized by uncontrolled lipid peroxidation, is involved in the progression of NASH. Nitric oxide (NO) is a versatile biological molecule that can degrade extracellular matrix. In this study, we developed a PEGylated thiolated hollow mesoporous silica nanoparticles (MSN) loaded with OCA, as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S -nitrosothiol (ONL@MSN). Biochemical analyses, histology, multiplexed flow cytometry, bulk-tissue RNA sequencing, and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle (ONL@MSN) in a mouse NASH model. Compared with the OCA-loaded nanoparticles (O@MSN), ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ferroptosis. ONL@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis, inhibition of immune response/lipid peroxidation, and correction of microbiota dysbiosis. These findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR, ferroptosis, and fibrosis. The PEGylated and thiolated hollow mesoporous silica nanoparticles (MSN), loaded with OCA, S -nitrosothiol, and liproxstatin-1, exhibit potent therapeutic action against NASH by simultaneously targeting FXR, ferroptosis, and fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Glaucoma valves (GVs) play an essential role in treating glaucoma. However, fibrosis after implantation has limited their long-term success in clinical applications. In this study, we aimed to develop a comprehensive surface-engineering strategy to improve the biocompatibility of GVs by constructing a microenvironment-regulated and dual-hydrophilic antifouling coating on a GV material (silicone rubber, SR). The coating was based on a superhydrophilic polydopamine (SPD) coating with good short-range superhydrophilicity and antifouling abilities. In addition, SPD coatings contain many phenolic hydroxyl groups that can effectively resist oxidative stress and the inflammatory microenvironment. Furthermore, based on its in situ photocatalytic free-radical polymerization properties, the SPD coating polymerized poly 2-methylacryloxyethylphosphocholine, providing an additional long-range hydrophilic and antifouling effect. The in vitro test results showed that the microenvironment-regulated and dual-hydrophilic coatings had anti-protein contamination, anti-oxidation, anti-inflammation, and anti-fiber proliferation capabilities. The in vivo test results indicated that this coating substantially reduced the fiber encapsulation formation of the SR material by inhibiting inflammation and fibrosis. This design strategy for dual hydrophilic coatings with microenvironmental regulation can provide a valuable reference for the surface engineering design of novel medical implantable devices. Superhydrophilic polydopamine (SPD) coatings were prepared on silicone rubber (SR) by a two-electron oxidation method. Introduction of pMPC to SPD surface using photocatalytic radical polymerization to obtain a dual-hydrophilic coating. The dual-hydrophilic coating effectively modulates the oxidative and inflammatory microenvironment. This coating significantly reduced protein contamination and adhesion of inflammatory cells and fibroblasts in vitro. The coating-modified SR inhibits inflammatory and fibrosis responses in vivo , promising to serve the glaucoma valves. [Display omitted] [ABSTRACT FROM AUTHOR]

Salivary gland damage and hypofunction result from various disorders, including autoimmune Sjögren's disease (SjD) and IgG4-related disease (IgG4-RD), as well as a side effect of radiotherapy for treating head and neck cancers. There are no therapeutic strategies to prevent the loss of salivary gland function in these disorders nor facilitate functional salivary gland regeneration. However, ongoing aquaporin-1 gene therapy trials to restore saliva flow show promise. To identify and develop novel therapeutic targets, we must better understand the cell-specific signaling processes involved in salivary gland regeneration. Transforming growth factor-β (TGF-β) signaling is essential to tissue fibrosis, a major endpoint in salivary gland degeneration, which develops in the salivary glands of patients with SjD, IgG4-RD, and radiation-induced damage. Though the deposition and remodeling of extracellular matrix proteins are essential to repair salivary gland damage, pathological fibrosis results in tissue hardening and chronic salivary gland dysfunction orchestrated by multiple cell types, including fibroblasts, myofibroblasts, endothelial cells, stromal cells, and lymphocytes, macrophages, and other immune cell populations. This review is focused on the role of TGF-β signaling in the development of salivary gland fibrosis and the potential for targeting TGF-β as a novel therapeutic approach to regenerate functional salivary glands. The studies presented highlight the divergent roles of TGF-β signaling in salivary gland development and dysfunction and illuminate specific cell populations in damaged or diseased salivary glands that mediate the effects of TGF-β. Overall, these studies strongly support the premise that blocking TGF-β signaling holds promise for the regeneration of functional salivary glands. [Display omitted] [ABSTRACT FROM AUTHOR]

Salivary gland hypofunction is highly prevalent in aged and diseased individuals leading to significant discomfort and morbidity. One factor that contributes to salivary gland hypofunction is cellular aging, or senescence. Senescent cells can impair gland function by secreting paracrine-acting growth factors and cytokines, known as senescence-associated secretory phenotype (SASP) factors. These SASP factors stimulate inflammation, propagate the senescent phenotype through the bystander effect, and stimulate fibrosis. As senotherapeutics that target senescent cells have shown effectiveness in limiting disease manifestations in other conditions, there is interest in the use of these drugs to treat salivary gland hypofunction. In this review, we highlight the contribution of senescence and fibrosis to salivary gland pathologies. We also discuss therapeutic approaches to eliminate or modulate the senescent SASP phenotype for treating age-related salivary gland diseases and extending health span. [Display omitted] [ABSTRACT FROM AUTHOR]

• Secretome from M1 and M2 macrophages were generated to treat keloid fibroblasts. • M2 secretome enhances the fibrogenic profile of keloid fibroblasts. • M1 secretome attenuates the fibrogenic profile of keloid fibroblasts. • M1 secretome prevents from profibrotic effect of TGF-β1 in keloid fibroblasts. • First demonstration that M1/M2 macrophages differentially impact fibrogenesis in keloid. Keloid refers to a fibroproliferative disorder characterized by an accumulation of extracellular matrix (ECM) components at the dermis level, overgrowth beyond initial wound, and formation of tumor-like nodule areas. Treating keloid is still an unmet clinical need and the lack of an efficient therapy is clearly related to limited knowledge about keloid etiology, despite the growing interest of the scientific community in this pathology. In past decades, keloids were often studied in vitro through the sole prism of fibroblasts considered as the major effector of ECM deposition. Nevertheless, development of keloids results from cross-interactions of keloid fibroblasts (KFs) and their surrounding microenvironment, including immune cells such as macrophages. Our study aimed to evaluate the effect of M1 and M2 monocyte-derived macrophages on KFs in vitro. We focused on the effects of the macrophage secretome on fibrosis-related criteria in KFs, including proliferation, migration, differentiation, and ECM synthesis. First, we demonstrated that M2-like macrophages enhanced the fibrogenic profile of KFs in culture. Then, we surprisingly founded that M1-like macrophages can have an anti-fibrogenic effect on KFs, even in a pro-fibrotic environment. These results demonstrate, for the first time, that M1 and M2 macrophage subsets differentially impact the fibrotic fate of KFs in vitro , and suggest that restoring the M1/M2 balance to favor M1 in keloids could be an efficient therapeutic lever to prevent or treat keloid fibrosis. [ABSTRACT FROM AUTHOR]

• Fibrosis is a common trait of cardiomyopathies reflecting shared pathogenesis. • Abnormal extracellular matrix remodeling is linked to fibrosis in cardiomyopathies. • The diversity of cardiomyopathies requires novel tools for diagnosis and treatment. • Extracellular matrix can serve as a source of novel biomarkers and drug targets. • Multidisciplinary approaches show potential in improving cardiomyopathy management. Cardiomyopathies encompass a spectrum of heart disorders with diverse causes and presentations. Fibrosis stands out as a shared hallmark among various cardiomyopathies, reflecting a common thread in their pathogenesis. This prevalent fibrotic response is intricately linked to the consequences of dysregulated extracellular matrix (ECM) remodeling, emphasizing its significance in the development and progression the disease. This review explores the ECM involvement in various cardiomyopathies and its impact on myocardial stiffness and fibrosis. Additionally, we discuss the potential of ECM fragments as early diagnosis, prognosis, and risk stratification. Biomarkers deriving from turnover of collagens and other ECM proteins hold promise in clinical applications. We outline current clinical management, future directions, and the potential for personalized ECM-targeted therapies with specific focus on microRNAs. In summary, this review examines the role of the fibrosis in cardiomyopathies, highlighting the potential of ECM-derived biomarkers in improving disease management with implications for precision medicine. [ABSTRACT FROM AUTHOR]

• A chemical probe offers visualization of collagen remodelling in healing tissue. • The chemical probe targets newly formed collagen at the wound site. • We provide spatio-temporal insights into collagen changes during wound healing. • The chemical probe distinguishes between normal and altered wound healing. Tissue repair and fibrosis involve the dynamic remodeling of collagen, and accurate detection of these sites is of utmost importance. Here, we use a collagen peptide sensor (1) to visualize collagen formation and remodeling during wound healing in mice and humans. We show that the probe binds selectively to sites of collagen formation and remodeling at different stages of healing. Compared to conventional methods, the peptide sensor localizes preferentially to areas of collagen synthesis and remodeling at the wound edge and not in matured fibrillar collagen. We also demonstrate its applicability for in vivo wound imaging and for discerning differential remodeling in wounds of transgenic mice with altered collagen dynamics. Our findings show the value of 1 as a diagnostic tool to rapidly identify the sites of matrix remodeling in tissue sections, which will aid in the conception of new therapeutic strategies for fibrotic disorders and defective tissue repair. [ABSTRACT FROM AUTHOR]

To study the molecular mechanisms responsible for fibrosis in endometriosis by investigating whether the protein expression levels of sphingosine-1-phosphate receptor 3 (S1PR3), one of the five specific receptors of the bioactive sphingolipid sphingosine-1-phosphate (S1P), correlate with fibrosis extent in endometriotic lesions and which are the cellular mechanisms involved in this process. Case-control laboratory study and cultured endometriotic cells. University research institute and university hospital. A total of 33 women, with and without endometriosis, were included in the study. Endometriotic lesions were obtained from women with endometriosis (ovarian endometrioma, n = 8; deep infiltrating endometriosis, n = 15; [urological n = 5, gastrointestinal n = 6, and posterior n = 4]) and control endometrium from healthy women, n = 10, by means of laparoscopic and hysteroscopic surgery. The expression of S1PR3 was evaluated using immunohistochemistry and the extent of fibrosis was assessed using Masson's trichrome staining. Human-cultured epithelial endometriotic 12Z cells were used to evaluate the mechanisms involved in the profibrotic effect of S1PR3 activation. The expression of S1PR3 in endometriotic lesions is positively correlated with endometriosis-associated fibrosis. In addition, S1P induced epithelial-mesenchymal transition (EMT) and fibrosis in epithelial endometriotic cells. Using RNA interference and pharmacological approaches, the profibrotic effect of S1P was shown to rely on S1PR3, thus unveiling the molecular mechanism implicated in the profibrotic action of the bioactive sphingolipid. The protein expression levels of S1PR3 were significantly augmented in the glandular sections of endometrioma and deep infiltrating endometriosis of different localizations with respect to the control endometrium and positively correlated with the extent of fibrosis. Sphingosine-1-phosphate was shown to have a crucial role in the onset of fibrosis in epithelial endometriotic cells, stimulating the expression of EMT and fibrotic markers. Genetic approaches have highlighted that S1PR3 mediates the fibrotic effect of S1P. Downstream of S1PR3, ezrin and extracellular-signal-regulated kinases 1 and 2 signaling were found to be critically implicated in the EMT and fibrosis elicited by S1P. Sphingosine-1-phosphate receptor 3 may represent a possible innovative pharmacological target for endometriosis. [ABSTRACT FROM AUTHOR]

In steatotic liver diseases (SLDs), including metabolic dysfunction-associated SLD and alcohol-associated liver disease, the excessive hepatic metabolism of lipids and alcohol leads to an increase in hepatic mitochondrial reductive stress, which in turn contributes to the development of SLD. Recent genetic studies conducted on both humans and mice have provided further evidence highlighting the key role played by hepatic mitochondrial reductive stress in the pathogenesis of SLD. Several pharmaceutical agents currently in development for the treatment of SLD, such as peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers, share an under-recognized common characteristic in that they decrease hepatic mitochondrial reductive stress. A more comprehensive understanding of hepatic mitochondrial reductive stress could help elucidate disease pathogenesis and facilitate the identification of new therapeutic approaches. Steatotic liver diseases (SLDs) affect one-third of the population, but the pathogenesis underlying these diseases is not well understood, limiting the available treatments. A common factor in SLDs is increased hepatic mitochondrial reductive stress, which occurs as a result of excessive lipid and alcohol metabolism. Recent research has also shown that genetic risk factors contribute to this stress. This review aims to explore how these risk factors increase hepatic mitochondrial reductive stress and how it disrupts hepatic metabolism, leading to SLDs. Additionally, the review will discuss the latest clinical studies on pharmaceutical treatments for SLDs, specifically peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor (THR) agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers. These treatments have a common effect of decreasing hepatic mitochondrial reductive stress, which has been largely overlooked. [ABSTRACT FROM AUTHOR]

IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder characterized by elevated IgG4 serum levels, abundant IgG4-positive plasmacyte infiltration, and fibrosis of various organs, including the head and neck. We aimed to provide an overall review of IgG4-RD in the sinonasal region and propose a novel entity and criteria of chronic rhinosinusitis (CRS) associated with IgG4-RD as "IgG4-CRS," a distinct manifestation of IgG4-RD in the sinonasal region. Sinonasal involvement has been increasingly recognized; however, this region is not included in the classic IgG4-RD-affected organs. The clinical features of IgG4-CRS, including its prevalence and relationship with allergies and olfactory disturbances, have also been explored. Serum IgG4 levels and IgG4-positive plasma cell infiltrations, crucial diagnostic factors, have been discussed in association with IgG4-CRS pathogenesis. Fibrosis, a hallmark of IgG4-RD, is observed in sinonasal tissues; however, typical fibrosis, such as storiform fibrosis, is not usually found. Mimics or complications in eosinophilic CRS (ECRS) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are highlighted. Treatment often involves typically effective glucocorticoids. Organ-specific diagnostic criteria for the sinonasal region have not currently been established. Hence, this review aims to foster awareness and understanding of IgG4-CRS among ENT physicians and to provide a basis for future research and diagnostic refinement. [ABSTRACT FROM AUTHOR]

[Display omitted] IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3+ T or CD19+ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T-cell and CD19+ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells or GZMK+CD8+ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-β but did not express immune checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD−CD27−CD11c−CXCR5− double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ cytotoxic T cells colocalized with MKI67+ B cells in the extrafollicular area from affected tissue sites. The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGF-β in the pathogenesis of inflammatory fibrotic disorders. [ABSTRACT FROM AUTHOR]

Peritoneal mesothelial cell senescence promotes the development of peritoneal dialysis (PD)-related peritoneal fibrosis. We previously revealed that Brahma-related gene 1 (BRG1) is increased in peritoneal fibrosis yet its role in modulating peritoneal mesothelial cell senescence is still unknown. This study evaluated the mechanism of BRG1 in peritoneal mesothelial cell senescence and peritoneal fibrosis using BRG1 knockdown mice, primary peritoneal mesothelial cells and human peritoneal samples from PD patients. The augmentation of BRG1 expression accelerated peritoneal mesothelial cell senescence, which attributed to mitochondrial dysfunction and mitophagy inhibition. Mitophagy activator salidroside rescued fibrotic responses and cellular senescence induced by BRG1. Mechanistically, BRG1 was recruited to oxidation resistance 1 (OXR1) promoter, where it suppressed transcription of OXR1 through interacting with forkhead box protein p2. Inhibition of OXR1 abrogated the improvement of BRG1 deficiency in mitophagy, fibrotic responses and cellular senescence. In a mouse PD model, BRG1 knockdown restored mitophagy, alleviated senescence and ameliorated peritoneal fibrosis. More importantly, the elevation level of BRG1 in human PD was associated with PD duration and D/P creatinine values. In conclusion, BRG1 accelerates mesothelial cell senescence and peritoneal fibrosis by inhibiting mitophagy through repression of OXR1. This indicates that modulating BRG1-OXR1-mitophagy signaling may represent an effective treatment for PD-related peritoneal fibrosis. [Display omitted] • BRG1 promotes cellular senescence and fibrotic response in peritoneal mesothelial cells. • BRG1 promotes mitochondrial impairment. • BRG1 accelerates cellular senescence and fibrotic response through inhibiting mitophagy. • BRG1 inhibits mitophagy by suppressing OXR1 through interacting with Foxp2. [ABSTRACT FROM AUTHOR]

The study aimed to describe the prevalence, severity, and trajectory of internal lymphedema, external lymphedema, and fibrosis in patients with oral cavity or oropharyngeal (OCOP) cancer. One hundred twenty patients with newly diagnosed OCOP cancer were enrolled in a prospective longitudinal study. Recruitment was conducted at a comprehensive medical center. Participants were assessed pretreatment; at end of treatment; and at 3, 6, 9, and 12 months post–cancer treatment. Validated clinician-reported measures and computed tomography were used to assess the study outcomes. Seventy-six patients who completed the 9- or 12-month assessments were included in this report. Examination of the external lymphedema and fibrosis trajectories revealed that the total severity score peaked between the end of treatment and 3 months posttreatment and then decreased gradually over time but did not return to baseline by 12 months posttreatment (P <.001). The longitudinal patterns of severity scores for patients treated with surgery only or with multimodality therapy were similar. Examination of the internal swelling trajectories revealed that all patients experienced a significant increase in sites with swelling immediately posttreatment. For patients treated with surgery only, swelling was minimal and returned to baseline by 9 to 12 months posttreatment. Patients receiving multimodal treatment experienced a gradual decrease in number of sites with swelling during the 12-month posttreatment period that remained significantly above baseline (P <.05). Computed tomography revealed different patterns of changes in prevertebral soft tissue and epiglottic thickness in the surgery-only and multimodality treatment groups during the 12-month posttreatment period. There were minimal changes in thickness in both regions in the surgery-only group. Patients with multimodal treatment had significant increases in thickness in both regions 3 months posttreatment that remained thicker at 12 months than at baseline (P <.001). Lymphedema and fibrosis are the common complications of OCOP cancer therapy. Routine assessment, monitoring, and timely treatment of lymphedema and fibrosis are critical. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF), for which effective treatments are limited, results in excessive and disorganized deposition of aberrant extracellular matrix (ECM). An altered ECM microenvironment is postulated to contribute to disease progression through inducing profibrotic behavior of lung fibroblasts, the main producers and regulators of ECM. Here, we examined this hypothesis in a 3D in vitro model system by growing primary human lung fibroblasts in ECM-derived hydrogels from non-fibrotic (control) or IPF lung tissue. Using this model, we compared how control and IPF lung-derived fibroblasts responded in control and fibrotic microenvironments in a combinatorial manner. Culture of fibroblasts in fibrotic hydrogels did not alter in the overall amount of collagen or glycosaminoglycans but did cause a drastic change in fiber organization compared to culture in control hydrogels. High-density collagen percentage was increased by control fibroblasts in IPF hydrogels at day 7, but decreased at day 14. In contrast, IPF fibroblasts only decreased the high-density collagen percentage at day 14, which was accompanied by enhanced fiber alignment in IPF hydrogels. Similarly, stiffness of fibrotic hydrogels was increased only by control fibroblasts by day 14 while those of control hydrogels were not altered by fibroblasts. These data highlight how the ECM-remodeling responses of fibroblasts are influenced by the origin of both the cells and the ECM. Moreover, by showing how the 3D microenvironment plays a crucial role in directing cells, our study paves the way in guiding future investigations examining fibrotic processes with respect to ECM remodeling responses of fibroblasts. In this study, we investigated the influence of the altered extracellular matrix (ECM) in Idiopathic Pulmonary Fibrosis (IPF), using a 3D in vitro model system composed of ECM-derived hydrogels from both IPF and control lungs, seeded with human IPF and control lung fibroblasts. While our results indicated that fibrotic microenvironment did not change the overall collagen or glycosaminoglycan content, it resulted in a dramatically alteration of fiber organization and mechanical properties. Control fibroblasts responded differently from IPF fibroblasts, highlighting the unique instructive role of the fibrotic ECM and the interplay with fibroblast origin. These results underscore the importance of 3D microenvironments in guiding pro-fibrotic responses, offering potential insights for future IPF therapies as well as other fibrotic diseases and cancer. [Display omitted] [ABSTRACT FROM AUTHOR]