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Background: Interstitial lung diseases (ILDs) include a large number of diseases associated with progressive pulmonary fibrosis (PPF), including idiopathic pulmonary fibrosis (IPF). Despite the rarity of each of the fibrotic ILDs individually, they cumulatively affect a considerable number of patients. PPF is characterised by an excessive collagen deposition leading to functional decline., Objectives: Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression. CD206-expressing M2 macrophages are involved in fibrosis progression, and whether they may be relevant therapeutic targets or biomarkers remains an open question., Results: In our study, CD206 + lung macrophages were monitored in bleomycin-induced lung fibrosis in mice by combining flow cytometry, scRNAseq and in vivo molecular imaging using a single photon emission computed tomography (SPECT) radiopharmaceutical, 99m Tc-tilmanocept. The antifibrotic effect of the inhibition of M2 macrophage polarisation with a JAK inhibitor, tofacitinib, was assessed in vivo. We demonstrate that CD206-targeted in vivo SPECT imaging with 99m Tc-tilmanocept was able to accurately detect and quantify the increase in CD206 + macrophages from early to advanced stages of experimental fibrosis and ex vivo in lung biopsies from patients with IPF. CD206-targeted imaging also specifically detected a decrease in CD206 + lung macrophages on nintedanib and tofacitinib treatment. Importantly, early in vivo imaging of CD206 + macrophages allowed the prediction of experimental lung fibrosis progression as well as nintedanib and tofacitinib efficacy., Conclusions: These findings indicate that M2 macrophages may be relevant theranostic targets for personalised medicine for patients with PPF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-β. Increased expression of CTGF has been observed in fibrotic lungs and inhibiting CTGF signaling has been shown to suppress lung fibrosis in several animal models. Thus, the CTGF signaling pathway is emerging as a potential therapeutic target in IPF and other pulmonary fibrotic conditions. This review provides a comprehensive overview of the current evidence on the pathogenic role of CTGF in pulmonary fibrosis and discusses the current therapeutic agents targeting CTGF using a systematic review approach., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-β1 (transforming growth factor-β1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2 , in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.

Idiopathic pulmonary fibrosis (IPF) is the representative phenotype of interstitial lung disease where severe scarring develops in the lung interstitium. Although antifibrotic treatments are available and have been shown to slow the progression of IPF, improved therapeutic options are still needed. Recent data indicate that macrophages play essential pro-fibrotic roles in the pathogenesis of pulmonary fibrosis. Historically, macrophages have been classified into two functional subtypes, "M1″ and "M2," and it is well described that "M2″ or "alternatively activated" macrophages contribute to fibrosis via the production of fibrotic mediators, such as TGF-β, CTGF, and CCL18. However, highly plastic macrophages may possess distinct functions and phenotypes in the fibrotic lung environment. Thus, M2-like macrophages in vitro and pro-fibrotic macrophages in vivo are not completely identical cell populations. Recent developments in transcriptome analysis, including single-cell RNA sequencing, have attempted to depict more detailed phenotypic characteristics of pro-fibrotic macrophages. This review will outline the role and characterization of pro-fibrotic macrophages in fibrotic lung diseases and discuss the possibility of treating lung fibrosis by preventing or reprogramming the polarity of macrophages. We also utilized a systematic approach to review the literature and identify novel and promising therapeutic agents that follow this treatment strategy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Particulate matter 2.5 μm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.5 composition with adverse outcomes remain unclear., Objective: To investigate the association of PM2.5 exposure with mortality and lung function among patients with fILD., Design, Setting, and Participants: In this multicenter, international, prospective cohort study, patients were enrolled in the Simmons Center for Interstitial Lung Disease Registry at the University of Pittsburgh in Pittsburgh, Pennsylvania; 42 sites of the Pulmonary Fibrosis Foundation Registry; and 8 sites of the Canadian Registry for Pulmonary Fibrosis. A total of 6683 patients with fILD were included (Simmons, 1424; Pulmonary Fibrosis Foundation, 1870; and Canadian Registry for Pulmonary Fibrosis, 3389). Data were analyzed from June 1, 2021, to August 2, 2022., Exposures: Exposure to PM2.5 and its constituents was estimated with hybrid models, combining satellite-derived aerosol optical depth with chemical transport models and ground-based PM2.5 measurements., Main Outcomes and Measures: Multivariable linear regression was used to test associations of exposures 5 years before enrollment with baseline forced vital capacity and diffusion capacity for carbon monoxide. Multivariable Cox models were used to test associations of exposure in the 5 years before censoring with mortality, and linear mixed models were used to test associations of exposure with a decrease in lung function. Multiconstituent analyses were performed with quantile-based g-computation. Cohort effect estimates were meta-analyzed. Models were adjusted for age, sex, smoking history, race, a socioeconomic variable, and site (only for Pulmonary Fibrosis Foundation and Canadian Registry for Pulmonary Fibrosis cohorts)., Results: Median follow-up across the 3 cohorts was 2.9 years (IQR, 1.5-4.5 years), with death for 28% of patients and lung transplant for 10% of patients. Of the 6683 patients in the cohort, 3653 were men (55%), 205 were Black (3.1%), and 5609 were White (84.0%). Median (IQR) age at enrollment across all cohorts was 66 (58-73) years. A PM2.5 exposure of 8 μg/m3 or more was associated with a hazard ratio for mortality of 4.40 (95% CI, 3.51-5.51) in the Simmons cohort, 1.71 (95% CI, 1.32-2.21) in the Pulmonary Fibrosis Foundation cohort, and 1.45 (95% CI, 1.18-1.79) in the Canadian Registry for Pulmonary Fibrosis cohort. Increasing exposure to sulfate, nitrate, and ammonium PM2.5 constituents was associated with increased mortality across all cohorts, and multiconstituent models demonstrated that these constituents tended to be associated with the most adverse outcomes with regard to mortality and baseline lung function. Meta-analyses revealed consistent associations of exposure to sulfate and ammonium with mortality and with the rate of decrease in forced vital capacity and diffusion capacity of carbon monoxide and an association of increasing levels of PM2.5 multiconstituent mixture with all outcomes., Conclusions and Relevance: This cohort study found that exposure to PM2.5 was associated with baseline severity, disease progression, and mortality among patients with fILD and that sulfate, ammonium, and nitrate constituents were associated with the most harm, highlighting the need for reductions in human-derived sources of pollution.

Background: This multicentre, international, prospective cohort study evaluated whether patients with pulmonary sarcoidosis living in neighbourhoods with greater material and social disadvantage experience worse clinical outcomes., Methods: The area deprivation index and the Canadian Index of Multiple Deprivation evaluate neighbourhood-level disadvantage in the US and Canada, with higher scores reflecting greater disadvantage. Multivariable linear regression evaluated associations of disadvantage with baseline forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide ( D LCO ) and linear mixed effects models for associations with rate of FVC or D LCO decline, and competing hazards models were used for survival analyses in the US cohort, evaluating competing outcomes of death or lung transplantation. Adjustments were made for age at diagnosis, sex, race and smoking history., Results: We included 477 US and 122 Canadian patients with sarcoidosis. Higher disadvantage was not associated with survival or baseline FVC. The highest disadvantage quartile was associated with lower baseline D LCO in the US cohort (β = -6.80, 95% CI -13.16 to -0.44, p=0.04), with similar findings in the Canadian cohort (β = -7.47, 95% CI -20.28 to 5.33, p=0.25); with more rapid decline in FVC and D LCO in the US cohort (FVC β = -0.40, 95% CI -0.70 to -0.11, p=0.007; D LCO β = -0.59, 95% CI -0.95 to -0.23, p=0.001); and with more rapid FVC decline in the Canadian cohort (FVC β = -0.80, 95% CI -1.37 to -0.24, p=0.003)., Conclusion: Patients with sarcoidosis living in high disadvantage neighbourhoods experience worse baseline lung function and more rapid lung function decline, highlighting the need for better understanding of how neighbourhood-level factors impact individual patient outcomes., Competing Interests: Conflict of interest: G.C. Goobie receives research funding and support through the Pulmonary Fibrosis Foundation Scholars Award Program and the University of British Columbia Clinician Investigator Program. C.J. Ryerson, D. Assayag and M.R.J. Kolb report personal fees and grants from Boehringer Ingelheim and Hoffman La Roche outside the submitted work. K.A. Johannson reports personal fees, nonfinancial support and other support from Boehringer Ingelheim and the Three Lakes Foundation, personal fees from Hoffman-La Roche Ltd, and grants from the University Hospital Foundation, the University of Calgary Cumming School of Medicine, and the Pulmonary Fibrosis Society of Calgary. V. Marcoux reports grants and personal fees from Boehringer Ingelheim Canada, Hoffman La-Roche Ltd and AstraZeneca, and grants from the University of Saskatchewan and the Royal University Hospital Foundation. M.R.J. Kolb also reports personal fees and grants from GSK, Gilead, Actelion, Respivert, Genoa, Alkermes, Pharmaxis, Prometric, Indalo and Third Pole. H. Manganas reports grants from Hoffman-La Roche Ltd, Galapagos and BMS, and personal fees and research grants from Boehringer Ingelheim. D. Assayag also reports personal fees and grants from Novartis. J.H. Fisher reports grants from the Canadian Pulmonary Fibrosis Foundation, and personal fees from Boehringer Ingelheim and AstraZeneca, outside of the submitted work. D.J. Kass is supported in part by AR060780, HL133232, UL1 TR001857 and AR076024 (NIH grants), Boehringer Ingelheim grants, and receives collaborative research funding from Regeneron Pharmaceuticals, outside of the submitted work. Y. Zhang is supported in part by AR076024 (NIH grant). S. Keil, E. Schikowski, N. Khalil, X. Chen, K.F. Gibson and K.O. Lindell report no competing interests. S.M. Nouraie receives grant support from Boehringer Ingelheim USA., (Copyright ©The authors 2022.)

Idiopathic pulmonary fibrosis is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and in the lung. Connective-tissue growth factor (CTGF) exacerbates pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we demonstrate upregulation of CTGF in a rat lung fibrosis model induced by an adenovirus vector encoding active TGF-β1 (AdTGF-β1). We show that CTGF is also upregulated in patients with idiopathic pulmonary fibrosis. Expression of CTGF was upregulated in vascular smooth muscle cells cultured from fibrotic lungs on Days 7 and 14 as well as endothelial cells sorted from fibrotic lungs on Days 14 and 28. These findings suggest contributions of different cells in maintaining the fibrotic phenotype during fibrogenesis. Treatment of fibroblasts with recombinant CTGF along with TGF-β increases profibrotic markers in fibroblasts, confirming the synergistic effect of recombinant CTGF with TGF-β in inducing pulmonary fibrosis. Also, the fibrotic extracellular matrix upregulated CTGF expression, compared with the normal extracellular matrix, suggesting that not only profibrotic mediators but also a profibrotic environment contributes to fibrogenesis. We also showed that pamrevlumab, a CTGF inhibitory antibody, partially attenuates fibrosis in the model. These results suggest that pamrevlumab could be an option for treatment of pulmonary fibrosis.

Rationale: Fibrotic interstitial lung disease (fILD) is a group of pathologic entities characterized by scarring of the lungs and high morbidity and mortality. Research investigating how socioeconomic and residential factors impact outcomes in patients with fILD is lacking. Objectives: To determine the association between neighborhood-level disadvantage and presentation severity, disease progression, lung transplantation, and mortality in patients with fILD from the United States and Canada. Methods: We performed a multicenter, international, prospective cohort study of 4,729 patients with fILD from one U.S. and eight Canadian ILD registry sites. Neighborhood-level disadvantage was measured by the area deprivation index in the United States and the Canadian Index of Multiple Deprivation in Canada. Measurements and Main Results: In the U.S. but not in the Canadian cohort, patients with fILD living in neighborhoods with the greatest disadvantage (top quartile) experience the highest risk of mortality (hazard ratio = 1.51, P  = 0.002), and in subgroups of patients with idiopathic pulmonary fibrosis, the top quartile of disadvantage experienced the lowest odds of lung transplantation (odds ratio = 0.46, P  = 0.04). Greater disadvantage was associated with reduced baseline DL CO in both cohorts, but it was not associated with baseline FVC or FVC or DL CO decline in either cohort. Conclusions: Patients with fILD who live in areas with greater neighborhood-level disadvantage in the United States experience higher mortality, and patients with idiopathic pulmonary fibrosis experience lower odds of lung transplantation. These disparities are not seen in Canadian patients, which may indicate differences in access to care between the United States and Canada.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high associated morbidity and mortality. The therapeutic landscape has significantly changed in the last 20 years with two drugs currently approved that have demonstrated the ability to slow disease progression. Despite these developments, survival in IPF is limited, so there is a major interest in therapeutic targets which could serve to open up new therapeutic avenues., Areas Covered: We review the most recent information regarding drug targets and therapies currently being investigated in preclinical and early-stage clinical trials., Expert Opinion: The complex pathogenesis of IPF and variability in disease course and response to therapy highlights the importance of a precision approach to therapy. Novel technologies including transcriptomics and the use of serum biomarkers, will become essential tools to guide future drug development and therapeutic decision making particularly as it pertains to combination therapy.

Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. We sought to investigate the role of FKBP13 (13-kD FK506-binding protein), an endoplasmic reticulum-resident molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy specimens from 24 patients with idiopathic pulmonary fibrosis and 17 control subjects. FKBP13 expression was found to be elevated in the fibrotic regions of idiopathic pulmonary fibrosis lung tissues and correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also increased in lung biopsy specimens of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using FKBP13 -/- mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 21), and resolution (Day 50) phases. FKBP13 -/- mice showed increased infiltration of inflammatory cells and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of fibrosis at Day 50. These changes were associated with an increased number of cells that stained positive for TUNEL and cleaved caspase 3 in the FKBP13 -/- lungs, indicating a heightened cellular sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity of interstitial lung diseases and that it has a biologically relevant role in protecting mice against bleomycin-induced injury, inflammation, and fibrosis.

The drug discovery pipeline, from discovery of therapeutic targets through preclinical and clinical development phases, to an approved product by health authorities, is a time-consuming and costly process, where a lead candidates' success at reaching the final stage is rare. Although the time from discovery to final approval has been reduced over the last decade, there is still potential to further optimize and streamline the evaluation process of each candidate as it moves through the different development phases. In this book chapter, we describe our preclinical strategies and overall decision-making process designed to evaluate the tolerability and efficacy of therapeutic candidates suitable for patients diagnosed with fibrotic lung disease. We also describe the benefits of conducting preliminary discovery trials, to aid in the selection of suitable primary and secondary outcomes to be further evaluated and assessed in subsequent internal and external validation studies. We outline all relevant research methodologies and protocols routinely performed by our research group and hope that these strategies and protocols will be a useful guide for biomedical and translational researchers aiming to develop safe and beneficial therapies for patients with fibrotic lung disease.

Purpose of Review: In this review, the authors describe therapeutic strategies for a disease group called progressive fibrosing interstitial lung disease (PF-ILD) and highlight the importance of the definition of progression, prognosis, and treatment response., Recent Findings: Although it is a relatively new concept, the term PF-ILD has been increasingly applied in clinical research and practice. Three domains commonly used to detect the disease progression include clinical symptoms, rate of forced vital capacity (FVC) decline and the extent of fibrosis on imaging. Although details of the pathogenesis of PF-ILD are still unclear, it has become apparent that genetic predisposition and an abnormal tissue microenvironment and host response are involved in the nature of the disease. Antifibrotic agents recently showed their efficacy on the treatment of PF-ILD. Both nintedanib and pirfenidone can slow the disease progression, as defined by a decline of FVC from baseline, of PF-ILD whenever compared with placebo, similar to the results in idiopathic pulmonary fibrosis (IPF) trials. This effect seems consistent irrespective of the underlying ILD diagnosis., Summary: Recent evidence supports the use of antifibrotic therapy in the management of the phenotype progressive non-IPF ILD. Ongoing studies exploring genetic and other molecular biomarkers could identify at-risk individuals or predict treatment response and prognosis (endotypes). This would support the concept of 'treatable traits' in the field of ILD.

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5-7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting <7 days after bleomycin installation) or therapeutic (>7 days). In addition, studies were cross-referenced with current major clinical trials to assess the availability of preclinical rationale.A total of 976 publications were evaluated. 726 investigated potential therapies, of which 443 (61.0%) were solely preventative, 166 (22.9%) were solely therapeutic and 105 (14.5%) were both. Of the 443 preventative studies, only 70 (15.8%) characterised inflammation during the model's early inflammatory phase. In the reported 145 IPF clinical trials investigating 93 compounds/combinations, only 25 (26.9%) interventions had any preclinical data on bleomycin available on PubMed.Since 2008, we observed a shift (from <5% to 37.4%) in the number of studies evaluating drugs in the therapeutic setting in the bleomycin model. While this shift is encouraging, further characterisation of early inflammation and appropriate preclinical therapeutic testing are still needed. This will facilitate fruitful drug development in IPF, and more therapeutic strategies for patients with this devastating disease., Competing Interests: Conflict of interest: P. Kolb has nothing to disclose. Conflict of interest: C. Upagupta has nothing to disclose. Conflict of interest: M. Vierhout has nothing to disclose. Conflict of interest: E. Ayaub has nothing to disclose. Conflict of interest: P.S. Bellaye has nothing to disclose. Conflict of interest: J. Gauldie has nothing to disclose. Conflict of interest: C. Shimbori has nothing to disclose. Conflict of interest: M. Inman has nothing to disclose. Conflict of interest: K. Ask reports grants from Boehringer Ingelheim, GSK, Prometic, Alkermes, Pharmaxis, Respivert, Indalo, Canadian Institutes for Health Research, Kniksa, Avalyn, National Sciences and Engineering Research Council, Ontario Thoracic Society, Canadian Pulmonary Fibrosis Foundation, Actelion, Gilead, Patara, Synairgen and Unity, outside the submitted work. Conflict of interest: M.R.J. Kolb reports grants and personal fees from Roche, Boehringer Ingelheim and Prometic, grants from GSK, Respivert, Alkermes, Pharmaxis and Canadian Institute for Health Research, personal fees from Genoa Indalo, Third Pole and Pieris, outside the submitted work, (Copyright ©ERS 2020.)

Background: The role of mast cells accumulating in idiopathic pulmonary fibrosis (IPF) lungs is unknown., Objectives: We investigated the effect of fibrotic extracellular matrix (ECM) on mast cells in experimental and human pulmonary fibrosis., Results: In IPF lungs, mast cell numbers were increased and correlated with disease severity (control vs 60%90% vs 60%90% vs FVC<60%, mean difference=-268.6, 95% CI of difference -441.0 to -96.17, p=0.0007). Plasma tryptase levels were increased in IPF and negatively correlated with FVC (control vs FVC<60%, mean difference=-17.12, 95% CI of difference -30.02 to -4.22, p=0.006: correlation curves R=-0.045, p=0.025). In a transforming growth factor (TGF)-β1-induced pulmonary fibrosis model, chymase-positive and tryptase-positive mast cells accumulated in fibrotic lung. Lung tissue was decellularised and reseeded with bone marrow or peritoneum-derived mast cells; cells on fibrotic ECM released more TGF-β1 compared with normal ECM (active TGF-β1: bone marrow-derived mast cell (BMMC)-DL vs BMMC-TGF-β1 p=0.0005, peritoneal mast cell (PMC)-DL vs PMC-TGF-β1 p=0.0003, total TGF-β1: BMMC-DL vs BMMC-TGF-β1 p=0.013, PMC-DL vs PMC-TGF-β1 p=0.001). Mechanical stretch of lungs caused mast cell degranulation; mast cell stabilisers inhibited degranulation (histamine: cont vs doxantrazole p=0.004, β-hexosaminidase: cont vs doxantrazole, mean difference=1.007, 95% CI of difference 0.2700 to 1.744, p=0.007) and TGF-β1 activation (pSmad2/Smad2: cont vs dox p=0.006). Cromoglycate attenuated pulmonary fibrosis in rats (collagen: phosphate-buffered saline (PBS) vs cromoglycate p=0.036, fibrotic area: PBS vs cromoglycate p=0.031)., Conclusion: This study suggests that mast cells may contribute to the progression of pulmonary fibrosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Although recent evidence has shown that IL-6 is involved in enhanced alternative activation of macrophages toward a profibrotic phenotype, the mechanisms leading to their increased secretory capacity are not fully understood. Here, we investigated the effect of IL-6 on endoplasmic reticulum (ER) expansion and alternative activation of macrophages in vitro. An essential mediator in this ER expansion process is the IRE1 pathway, which possesses a kinase and endoribonuclease domain to cleave XBP1 into a spliced bioactive molecule. To investigate the IRE1-XBP1 expansion pathway, IL-4/IL-13 and IL-4/IL-13/IL-6-mediated alternative programming of murine bone marrow-derived and human THP1 macrophages were assessed by arginase activity in cell lysates, CD206 and arginase-1 expression by flow cytometry, and secreted CCL18 by ELISA, respectively. Ultrastructural intracellular morphology and ER biogenesis were examined by transmission electron microscopy and immunofluorescence. Transcription profiling of 128 genes were assessed by NanoString and Pharmacological inhibition of the IRE1-XBP1 arm was achieved using STF-083010 and was verified by RT-PCR. The addition of IL-6 to the conventional alternative programming cocktail IL-4/IL-13 resulted in increased ER and mitochondrial expansion, profibrotic profiles and unfolded protein response-mediated induction of molecular chaperones. IRE1-XBP1 inhibition substantially reduced the IL-6-mediated hyperpolarization and normalized the above effects. In conclusion, the addition of IL-6 enhances ER expansion and the profibrotic capacity of IL-4/IL-13-mediated activation of macrophages. Therapeutic strategies targeting IL-6 or the IRE1-XBP1 axis may be beneficial to prevent the profibrotic capacity of macrophages., (© 2018 The Authors Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc.)

Introduction: Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive, and irreversible fatal interstitial lung disease. Although many drugs have failed in clinical trials, these failures improved the understanding of the pathogenesis of IPF. Currently, there are two drugs approved for IPF that slow the progression of the disease. However, the prognosis for patients with IPF remains poor and the search continues for drugs that inhibit the pathogenic pathways active in IPF to further reduce or even halt the progression of the disease., Areas Covered: We highlight the recent information on the therapeutic targets currently explored in early stage clinical trials and discuss the potential for new therapy and the limitation of basic research in the treatment of IPF., Expert Opinion: A key challenge in the coming years will lie in deciding which compounds to combine and how to evaluate combination therapies in clinical trials. The drugs most likely to provide additive efficacy when used in combination with one of the approved therapies are those with alternative, complementary, or synergistic mechanisms of action.

Although recent evidence indicates that gp130 cytokines, Oncostatin M (OSM) and IL-6 are involved in alternative programming of macrophages, their role in lung fibrogenesis is poorly understood. Here, we investigated the effect of transient adenoviral overexpression of OSM or IL-6 in mice during bleomycin-induced lung fibrosis. Lung fibrosis and M2-like macrophage accumulation were assessed by immunohistochemistry, western blotting, gene expression and flow cytometry. Ex-vivo isolated alveolar and bone marrow-derived macrophages were examined for M2-like programming and signalling. Airway physiology measurements at day 21 demonstrated that overexpression of OSM or IL-6 exacerbated bleomycin-induced lung elastance, consistent with histopathological assessment of extracellular matrix and myofibroblast accumulation. Flow cytometry analysis at day 7 showed increased numbers of M2-like macrophages in lungs of mice exposed to bleomycin and OSM or IL-6. These macrophages expressed the IL-6Rα, but were deficient for OSMRβ, suggesting that IL-6, but not OSM, may directly induce alternative macrophage activation. In conclusion, the gp130 cytokines IL-6 and OSM contribute to the accumulation of profibrotic macrophages and enhancement of bleomycin-induced lung fibrosis. This study suggests that therapeutic strategies targeting these cytokines or their receptors may be beneficial to prevent the accumulation of M2-like macrophages and the progression of fibrotic lung disease.