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SSc-ILD (scleroderma associated interstitial lung disease) is a complex rheumatic disease characterized in part by immune dysregulation leading to the progressive fibrotic replacement of normal lung architecture. Because improved treatment options are sorely needed, additional study of the fibroproliferative mechanisms mediating this disease has the potential to accelerate development of novel therapies. The contribution of innate immunity is an emerging area of investigation in SSc-ILD as recent work has demonstrated the mechanistic and clinical significance of the NLRP3 inflammasome and its associated cytokines of TNFα (tumor necrosis factor alpha), IL-1β (interleukin-1 beta), and IL-18 in this disease. In this review, we will highlight novel pathophysiologic insights afforded by these studies and the potential of leveraging this complex biology for clinical benefit.

Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of sterol regulatory element binding protein (SREBP) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti–miR-33 peptide nucleic acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.

More than 87% of patients report the persistence of at least one symptom after recovery from the Coronavirus disease 2019 (COVID-19). Dyspnea is one of the most frequently reported symptoms following severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) infection with persistent chest radiological abnormalities up to 3 months after symptom onset. These radiological abnormalities are variable and most commonly include ground-glass opacities, reticulations, mosaic attenuation, parenchymal bands, interlobular septal thickening, bronchiectasis, and fibrotic-like changes. However, in this case report, we describe findings of bullous lung disease as a complication of SARS CoV-2 infection. As the pandemic continues, there is a need to understand the multiple respiratory manifestations of post-acute sequelae of COVID-19. We, therefore, present this case to add to the current body of literature describing pulmonary disease as a consequence of SARS CoV-2 infection.

Excess macrophages and smooth muscle cells (SMCs) characterize many cardiovascular diseases, but crosstalk between these cell types is poorly defined. Pulmonary hypertension (PH) is a lethal disease in which lung arteriole SMCs proliferate and migrate, coating the normally unmuscularized distal arteriole. We hypothesized that increased macrophage platelet-derived growth factor–B (PDGF-B) induces pathological SMC burden in PH. Our results indicate that clodronate attenuates hypoxia-induced macrophage accumulation, distal muscularization, PH, and right ventricle hypertrophy (RVH). With hypoxia exposure, macrophage Pdgfb mRNA was upregulated in mice, and LysM‑Cre mice carrying floxed alleles for hypoxia-inducible factor 1a, hypoxia-inducible factor 2a, or Pdgfb had reduced macrophage Pdgfb and were protected against distal muscularization and PH. Conversely, LysM‑Cre von-Hippel Lindaufl/fl mice had increased macrophage Hifa and Pdgfb and developed distal muscularization, PH, and RVH in normoxia. Similarly, Pdgfb was upregulated in macrophages from human idiopathic or systemic sclerosis–induced pulmonary arterial hypertension patients, and macrophage-conditioned medium from these patients increased SMC proliferation and migration via PDGF-B. Finally, in mice, orotracheal administration of nanoparticles loaded with Pdgfb siRNA specifically reduced lung macrophage Pdgfb and prevented hypoxia-induced distal muscularization, PH, and RVH. Thus, macrophage-derived PDGF-B is critical for pathological SMC expansion in PH, and nanoparticle-mediated inhibition of lung macrophage PDGF-B has profound implications as an interventional strategy for PH.

Abstract Background Sarcoidosis is a multisystem, chronic granulomatous disease of unknown etiology that predominantly affects the lungs. Pulmonary sarcoidosis classically presents with constitutional symptoms and computed tomographic scan findings of bilateral, symmetric micronodules in a peribronchovascular distribution with upper and middle lung zone predominance accompanied by bilateral, symmetric hilar lymphadenopathy. A solitary lung mass is a rare finding for pulmonary sarcoidosis, and with its associated constitutional symptoms, it strongly mimics a malignancy. We aimed to provide further insight into the broad differential diagnosis of a lung mass by describing our experiences in the care of a patient who presented with clinical and radiographic features of lung cancer who was ultimately found to have an atypical manifestation of stage II pulmonary sarcoidosis. Case presentation A 44-year-old African American woman with a history of childhood asthma and type 2 diabetes mellitus presented with shortness of breath. After being treated for a presumed asthma exacerbation with prednisone, she experienced worsening dyspnea, night sweats, and unintentional weight loss. Further evaluation revealed a large left lower lobe mass and hilar lymphadenopathy. A computed tomography-guided biopsy of the lung mass revealed a multifocal non-necrotizing granuloma with multinucleated giant cells. Although consistent with sarcoidosis, this finding could represent a sarcoid-like reaction secondary to an occult malignancy. A more extensive repeat biopsy via bronchoscopy and mediastinoscopy revealed granulomatous inflammation without evidence of malignancy or infection. These procedures confirmed the diagnosis of pulmonary sarcoidosis, and she was started on treatment with high-dose prednisone. Her treatment course was complicated by hyperglycemia necessitating insulin therapy, but after 3 months of therapy, she reported improvement in her dyspnea, and repeat imaging revealed a significant decrease in the size of the lung mass and lymphadenopathy. Given her clinical and radiographic response, she was continued on a prednisone taper. Conclusions Atypical manifestations of pulmonary sarcoidosis are diagnostically challenging because the clinical and radiographic features of the disease mimic those of a malignancy. We aimed to illustrate a unique etiology of a lung mass and the importance of maintaining a broad differential diagnosis. Nonetheless, with the possibility of a malignancy, a high index of suspicion is necessary for timely diagnosis and optimal management.

Vascular rings are congenital malformations of the aortic arch. A double aortic arch (DAA), the most common type of vascular ring, results from the failure of the fourth embryonic branchial arch to regress, leading to an ascending aorta that divides into a left and right arch that fuse together to completely encircle the trachea and esophagus. The subsequent DAA causes compressive effects on the trachea and esophagus that typically manifests in infancy or early childhood. Adult presentations, particularly in the elderly, are exceedingly rare. Historically such patients have a long-standing history of dyspnea on exertion and dysphagia, with many assumed to have obstructive lung or intrinsic cardiac disease. We describe a case of an elderly woman who presented with respiratory failure due to DAA. In her case, surgery was not feasible and we describe our experience with airway stenting.

The article explores vascular changes in nonspecific interstitial pneumonia (NSIP), a lung disease. It reveals a significant replacement of normal lung capillaries with COL15A1-positive endothelial cells in NSIP patients, potentially affecting gas exchange and lung permeability. It further underscores the need for further research on the role of COL15A1 in lung fibrosis and its implications for fibrotic lung diseases.

Idiopathic pulmonary fibrosis is increasingly associated with nerve-driven processes and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here, we report that noradrenaline (NA) derived from the lung's adrenergic nerve supply drives a-smooth muscle actin (aSMA)-expressing fibroblast accumulation via mechanisms involving a1 adrenoreceptors and mtDNA. Using the bleomycin model, we compared ablation of the lung's adrenergic nerve supply with surgical adrenal resection and found that NA derived from local but not adrenal sources contributes to experimentally induced lung fibrosis and the emergence of an aSMAþve fibroblast population expressing adrenoreceptor a-1D (ADRA1D). Therapeutic delivery of the a1 adrenoreceptor antagonist terazosin reversed these changes and suppressed extracellular mtDNA accumulation. Cultured normal human lung fibroblasts displayed a1 adrenoreceptors and in response to costimulation with TGFb1 and NA adopted ACTA2 expression and extracellular mtDNA release. These findings were opposed by terazosin. Evaluation of a previously studied IPF cohort revealed that patients prescribed a1 adrenoreceptor antagonists for nonpulmonary indications demonstrated improved survival and reduced concentrations of plasma mtDNA. Our observations link nerve-derived NA, a1 adrenoreceptors, extracellular mtDNA, and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuroinnate connection may yield new avenues for investigation in the clinical and basic science realms. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a chronic granulomatous disease of unknown etiology that primarily affects the lungs. The development of stage IV or fibrotic lung disease accounts for a significant proportion of the morbidity and mortality attributable to sarcoidosis. Further investigation into the active mechanisms of disease pathogenesis and fibrogenesis might illuminate fundamental mediators of injury and repair while providing new opportunities for clinical intervention. However, progress in sarcoidosis research has been hampered by the heterogeneity of clinical phenotypes and the lack of a consensus modeling system. Recently, reverse translational research, wherein observations made at the patient level catalyze hypothesis-driven research at the laboratory bench, has generated new discoveries regarding the immunopathogenic mechanisms of pulmonary granuloma formation, fibrogenesis, and disease model development. The purpose of this review is to highlight the promise and possibility of these novel investigative efforts. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,60-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 (Gdf15), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15, and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes. [ABSTRACT FROM AUTHOR]

Rationale: Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 (TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF.Objectives: We aimed to define an association between mtDNA and fibroblast responses in IPF.Methods: We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-β1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects.Measurements and Main Results: Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-β1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival.Conclusions: These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: Laryngeal sarcoidosis is a rare extrapulmonary manifestation of sarcoidosis, accounting for 0.33-2.1% of cases. A life-threatening complication of laryngeal sarcoidosis is upper airway obstruction. In this report we describe our experience in the acute and chronic care of a patient who required an emergent tracheostomy, with the aim to provide further insight into this difficult to manage disease. Case Report: A 37-year-old African American female with a 10-year history of stage 1 sarcoidosis presented with severe dyspnea. Laryngeal sarcoidosis was diagnosed three years previously, and she remained stable on low-dose prednisone until six months prior to admission, at which time she self-discontinued her prednisone for the homeopathic treatment Nopalea cactus juice. Her physical examination was concerning for impending respiratory failure as she presented with inspiratory stridor and hoarseness. Laryngoscopy showed a retroflexed epiglottis obstructing the glottis with edematous arytenoids and aryepiglottic folds. Otolaryngology performed an emergent tracheostomy to secure her airway and obtained epiglottic biopsies, which were consistent with sarcoidosis. She was eventually discharged home on prednisone 60 mg daily. Following months of corticosteroids, a laryngoscopy showed the epiglottis continuing to obstruct the glottis. The addition of methotrexate to a tapered dosage of prednisone 10 mg daily was unsuccessful, and she remains on prednisone 20 mg daily for disease control. Conclusions: Laryngeal sarcoidosis, a rare extrapulmonary manifestation of sarcoidosis, uncommonly presents as the lifethreatening complication of complete upper airway obstruction. As such, laryngeal sarcoidosis is associated with significant morbidity and mortality, requiring a high index of suspicion for timely diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy. [ABSTRACT FROM AUTHOR]