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Sarcoidosis is a granulomatous disease of unknown etiology, with limited therapeutic options. Chronic sarcoidosis can result in pulmonary fibrosis and can be lethal. Enhanced expression of pro-inflammatory cytokines, such as interleukin-17A (IL-17A), has been observed in sarcoid granulomas in humans. However, the role of IL-17A in the pathogenesis of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis and its potential therapeutic effects remain unclear. This study investigated whether IL-17A is critical in granulomatosis and its role in chronic inflammation in a profibrotic manner. Wild-type and IL-17A-knockout C57BL/6 mice were repeatedly challenged with heat-killed Propionibacterium acnes (PA) to induce sarcoidosis-like granulomata and sarcoidosis-related pulmonary fibrosis. Wild-type mice with granulomatosis were treated with anti-IL-17A antibody. Administration of PA enhanced the expression of IL-17A, granulomatosis, and fibrosis in mouse lungs after boost stimulation. Neither granulomata nor fibrosis were observed in IL-17A-knockout mice, even in the presence of interferon-γ enhancement. Neutralizing IL-17A antibody reduced inflammatory cells in bronchoalveolar lavage fluid and ameliorated both granulomatosis and fibrosis in sarcoidosis mice. In conclusion, our data demonstrate that IL-17A plays a critical role in PA-induced sarcoidosis-like inflammation in both granulomatosis inflammation and disease progression to pulmonary fibrosis, thus providing novel insights into the treatment of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Myofibroblasts are the primary executor and influencer in lung fibrosis. Latest studies on lung myofibroblast pathobiology have significantly advanced the understanding of the pathogenesis of lung fibrosis and shed new light on strategies targeting these cells to treat this disease., Areas Covered: This article reviewed the most recent progresses, mainly within the last 5 years, on the definition, origin, activity regulation, and targeting of lung myofibroblasts in lung fibrosis. We did a literature search on PubMed using the keywords below from the dates 2010 to 2020., Expert Opinion: With the improved cell lineage characterization and the advent of scRNA-seq, the field is having much better picture of the lung myofibroblast origin and mesenchymal heterogeneity. Additionally, cellular metabolism has emerged as a key regulation of lung myofibroblast pathogenic phenotype and is a promising therapeutic target for treating a variety of lung fibrotic disorders.

Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through lactate regulating the pathogenic phenotype of alveolar macrophages. Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-β1 (transforming growth factor-β1)-induced lung myofibroblasts and in the BAL fluids (BALFs) from mice with TGF-β1- or bleomycin-induced lung fibrosis. Importantly, the media and BALFs promoted profibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the profibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and profibrotic gene expression were mediated by p300, as evidenced by their diminished concentrations in p300-knockdown macrophages. Collectively, our study establishes that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.

Recent studies have presented compelling evidence that it is not tissue-resident, but rather monocyte-derived alveolar macrophages (TR-AMs and Mo-AMs, respectively) that are essential to development of experimental lung fibrosis. However, whether apolipoprotein E (ApoE), which is produced abundantly by Mo-AMs in the lung, plays a role in the pathogenesis is unclear. In this study, we found that pulmonary ApoE was almost exclusively produced by Mo-AMs in mice with bleomycin-induced lung fibrosis. We showed that, although ApoE was not necessary for developing maximal fibrosis in bleomycin-injured lung, it was required for the resolution of this pathology. We found that ApoE directly bound to Collagen I and mediated Collagen I phagocytosis in vitro and in vivo, and this process was dependent on low-density lipoprotein receptor-related protein 1 (LPR1). Furthermore, interference of ApoE/LRP1 interaction impaired the resolution of lung fibrosis in bleomycin-treated WT mice. In contrast, supplementation of ApoE promoted this process in ApoE-/- animals. In conclusion, Mo-AM-derived ApoE is beneficial to the resolution of lung fibrosis, supporting the notion that Mo-AMs may have distinct functions in different phases of lung fibrogenesis. The findings also suggest a potentially novel therapeutic target for treating lung fibrosis, to which effective remedies remain scarce.

New Findings: • What is the central question of this study? The aim was to explore the effects and underlying mechanisms of H 2 on bleomycin-induced pulmonary fibrosis. • What are the main findings and its importance? Our results indicate that, in bleomycin-induced pulmonary fibrosis, H 2 inhalation attenuated oxidative stress and reversed the pulmonary epithelial-to-mesenchymal transition process by reducing reactive oxygen species production and inhibiting the expression of transforming growth factor-β1, α-smooth muscle actin and collagen I to improve fibrotic injury and exert anti-fibrogenic effects. Thus, H 2 inhalation has promising therapeutic potential as a useful adjuvant treatment for patients with idiopathic pulmonary fibrosis, which deserves further study and evaluation., Abstract: Hydrogen (H 2 ) can protect against tissue damage. The effect of H 2 inhalation therapy on the pathogenesis of pulmonary fibrosis remains unknown. This study was designed to explore the effects and underlying mechanisms of H 2 inhalation on bleomycin (BLM)-induced pulmonary fibrosis. A rat model of pulmonary fibrosis was established with BLM. Rats were randomly divided into control and H 2 inhalation groups. Haematoxylin and Eosin staining and Mason's Trichrome staining were performed to evaluate pulmonary fibrosis injury, inflammatory cell infiltration, structural disorder and collagen deposition. qRT-PCR and western blot assays were used to determine the expression of TNF-α, TGF-β1, α-SMA, E-cadherin, N-cadherin, vimentin, VEGF and collagen type I at both mRNA and protein levels. The contents of reactive oxygen species, TGF-β1, TNF-α, malondialdehyde and hydroxyproline were determined with biochemical test kits or ELISA kits. Bleomycin-stimulated rats exhibited typical symptoms of pulmonary fibrosis, which featured an increase in collagen deposition, alveolitis, fibrosis and parenchymal structural disorder in the lung. However, BLM-induced oxidative stress was attenuated by H 2 inhalation therapy, which reduced the contents of reactive oxygen species, malondialdehyde and hydroxyproline, enhanced the activity of glutathione peroxidase and decreased the expression of TGF-β1 and TNF-α. In addition, H 2 inhalation also inhibited BLM-induced epithelial-to-mesenchymal transition by inhibiting TGF-β1, increasing the expression level of the epithelial cell marker E-cadherin, and decreasing the expression level of the mesenchymal cell marker vimentin in a time-dependent manner. In addition, H 2 inhalation downregulated α-SMA expression and suppressed collagen I generation, exerting anti-fibrogenic effects. Hydrogen inhalation therapy attenuates BLM-induced pulmonary fibrosis by inhibiting TGF-β1, relevant oxidative stress and epithelial-to-mesenchymal transition., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

It has been increasingly recognized lately that aberrant cellular metabolism plays an important role in the pathogenesis of pulmonary fibrosis. In our previous systemic studies, we found that human lung myofibroblasts undergo glutaminolytic reprogramming, which is mediated by an increased expression of glutaminase (Gls) 1. We showed that augmented glutaminolysis critically regulates collagen production by promoting its stabilization in human lung myofibroblasts. Our study indicates that lung fibroblast Gls1 is a promising therapeutic target for this disease. In this investigation, we primarily focused on delineating the in vivo role of fibroblast Gls1 in mouse models of pulmonary fibrosis and determining the efficacy of Gls1 inhibition in treating this pathology. We now show that fibroblast Gls1 is upregulated in fibrotic mouse lungs. We present evidence that mice with ablation of fibroblast Gls1 are protected from bleomycin-induced lung fibrosis. We show that the Gls1 inhibitor, CB-839, is therapeutically efficacious in treating both bleomycin- and transforming growth factor-β1-induced pulmonary fibrosis. Our study has thus established a solid rationale for advancing Gls1 inhibitors, particularly CB-839, to the next stage of testing in the treatment of this disease.

Pulmonary fibrosis (PF) associated with chronic sarcoidosis remains poorly understood, and no experimental model is currently available for this condition. Previous studies have shown that Propionibacterium acnes (PA) was associated with sarcoidosis and induced granuloma formation in mice. Here, we investigated whether repeated challenge with PA induces persistent inflammation leading to sarcoidosis followed by PF in mice. Specifically, C57BL/6 mice were inoculated intraperitoneally and subjected to intratracheal challenge with PA, and then were booster-challenged with either PA or phosphate-buffered saline on day 28. Inflammation, granulomata, and features of fibrosis were evaluated every 7 days until day 70. Complete remission of lung granulomata was apparent on day 42 in the sarcoid-remission group. However, granulomata was present from days 21 to 70 in mice that received PA boosting. Inflammatory cell counts and Th1 cytokine levels in lung lavage fluids were elevated up to day 70. Furthermore, fibrotic changes in the lungs were observed around granulomatous and peribronchovascular regions after PA boosting. Taken together, these findings suggest that development of PF following sarcoidosis may result from continuous PA infection and inflammation. Repeated boosting with PA to induce PF might be a useful model for future studies of sarcoidosis-associated PF., Competing Interests: The authors declare no conflict of interest for this work.

The dysfunction of type II alveolar epithelial cells (AECIIs), mainly manifested by apoptosis, has emerged as a major component of idiopathic pulmonary fibrosis (IPF) pathophysiology. A pivotal mechanism leading to AECIIs apoptosis is mitochondrial dysfunction. Recently, interleukin (IL)‐17A has been demonstrated to have a pro‐fibrotic role in IPF, though the mechanism is unclear. In this study, we report enhanced expression of IL‐17 receptor A (IL‐17RA) in AECIIs in lung samples of IPF patients, which may be related to the accumulation of mitochondria in AECIIs of IPF. Next, we investigated this relationship in bleomycin (BLM)‐induced PF murine model. We found that IL‐17A knockout (IL‐17A−/−) mice exhibited decreased apoptosis levels of AECIIs. This was possibly a result of the recovery of mitochondrial morphology from the improved mitochondrial dynamics of AECIIs, which eventually contributed to alleviating lung fibrosis. Analysis of in vitro data indicates that IL‐17A impairs mitochondrial function and mitochondrial dynamics of mouse primary AECIIs, further promoting apoptosis. PTEN‐induced putative kinase 1 (PINK1)/Parkin signal‐mediated mitophagy is an important aspect of mitochondria homeostasis maintenance. Our data demonstrate that IL‐17A inhibits mitophagy and promotes apoptosis of AECIIs by decreasing the expression levels of PINK1. We conclude that IL‐17A exerts its pro‐fibrotic effects by inducing mitochondrial dysfunction in AECIIs by disturbing mitochondrial dynamics and inhibiting PINK1‐mediated mitophagy, thereby leading to apoptosis of AECIIs. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal fibrotic lung disease with largely unknown etiology and pathogenesis. Evidence suggests microRNAs (miRNA) contribute to pathogenesis of IPF. In this study, we sought to identify miRNA expression signatures and determine the role of miR-130b-3p in lung fibrosis. The miRNA expression profile of the lungs from patients with IPF and normal donors was determined by Affymetrix microarray, and transcriptome with Affymetrix array. The functions and signal pathways as well as miRNA-mRNA networks were established by bioinformatics analysis. Luciferase assays and ELISA were used to confirm the miRNA target gene. The effect of miRNA-transfected epithelium on fibroblast activities was assessed using a co-culture system. The fibroblast activities were determined by qRT-PCR, western blotting, Transwell and BrdU assays. Seven miRNAs were significantly decreased in IPF lungs, with miR-130b-3p being the highest in the miRNA-mRNA network. Insulin-like growth factor (IGF-1) was a target gene of miR-130b-3p in the epithelium. miR-130b-3p inhibition in the epithelium induced collagen I expression and enhanced the proliferation and migration ability of fibroblast in co-culture systems, which mimicked the functions of exogenous IGF-1 on fibroblasts. Neutralizing IGF-1 with an antibody significantly reduced the modulatory effects of miR-130b-3p inhibitor-transfected epithelium on the activation of fibroblasts. Our results show that miR-130b-3p was downregulated in IPF lungs. miR-130b-3p downregulation contributed to the activation of fibroblasts and the dysregulated epithelial-mesenchymal crosstalk by promoting IGF-1 secretion from lung epithelium, suggesting a key regulatory role for this miRNA in preventing lung fibrosis. [ABSTRACT FROM AUTHOR]