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Severe acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients. Eleven (11) critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE) and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG). Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial. Nine (9) trial subjects (82%) had improvements of pulmonary gas exchange after treatment, compared to one (5%) historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications. This pilot trial indicates specific treatments that reduce autoantibodies might benefit some severely-ill AE-IPF patients. These findings have potential implications regarding mechanisms of IPF progression, and justify considerations for incremental trials of autoantibody-targeted therapies in AE-IPF patients. ClinicalTrials.gov NCT01266317.

Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1 + SiglecF + transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury. Using scRNA-seq analysis, Bhattacharya and colleagues identify a subset of profibrotic lung macrophages that have a gene expression signature intermediate between those of monocytes and alveolar macrophages.

Reduced hyaluronan–TLR4 signaling in a stem cell population of the lung contributes to a lack of renewal of these cells and promotes fibrosis in patients with idiopathic pulmonary fibrosis. Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure.

Idiopathic pulmonary fibrosis (IPF) affects hundreds of thousands of people worldwide, reducing their quality of life and leading to death from respiratory failure within years of diagnosis. Treatment options remain limited, with only two FDA-approved drugs available in the United States, neither of which reverse the lung damage caused by the disease or prolong the life of individuals with IPF. The only cure for IPF is lung transplantation. In this review, we discuss recent major advances in our understanding of the role of the immune system in IPF that have revealed immune dysregulation as a critical driver of disease pathophysiology. We also highlight ways in which an improved understanding of the immune system's role in IPF may enable the development of targeted immunomodulatory therapies that successfully halt or potentially even reverse lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis. Idiopathic pulmonary fibrosis is associated with increased abundance of Staphylococcus and Streptococcus in the lungs. Here, the authors identify a Staphylococcus nepalensis -derived peptide, named corisin, to induce apoptosis of lung epithelial cells and exacerbation of pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is a prototype of lethal, chronic, progressive interstitial lung disease of unknown etiology. Over the past decade, macrophage has been recognized to play a significant role in IPF pathogenesis. Depending on the local microenvironments, macrophages can be polarized to either classically activated (M1) or alternatively activated (M2) phenotypes. In general, M1 macrophages are responsible for wound healing after alveolar epithelial injury, while M2 macrophages are designated to resolve wound healing processes or terminate inflammatory responses in the lung. IPF is a pathological consequence resulted from altered wound healing in response to persistent lung injury. In this review, we intend to summarize the current state of knowledge regarding the process of macrophage polarization and its mediators in the pathogenesis of pulmonary fibrosis. Our goal is to update the understanding of the mechanisms underlying the initiation and progression of IPF, and by which, we expect to provide help for developing effective therapeutic strategies in clinical settings.

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown. To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial. SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of ≥ 10% in FVC. Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (P interaction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort. NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.

Idiopathic pulmonary fibrosis (IPF) is a severe lung disease occurring throughout the world; however, few clinical therapies are available for treating this disorder. Overactivated fibroblasts drive abnormal fibrosis accumulation to maintain dynamic balance between inflammation and extracellular matrix (ECM) stiffness. Given pulmonary cell can regenerate, the lung may possess self-repairing abilities if fibrosis is removed via clearance of overactivated fibroblasts. The aim of this study was to evaluate the therapeutic activity of transient antifibrotic chimeric antigen receptor (CAR) T cells (generated via a novelly-designed lipid nanoparticle-messenger RNA (LNP-mRNA) system) and explore the regeneration mechanisms of lung in a male mouse model of bleomycin-induced pulmonary fibrosis. Here we found that fibrosis-induced ECM stiffening impaired alveolar epithelial cell compensation. The proposed LNP-mRNA therapy eliminated overactivated fibroblasts to rescue pulmonary fibrosis. The restored ECM environment regulated the cellular profile. The elevated plasticity of AT2 and Pclaf + cells increased AT1 cell population via polarization. Apoe + macrophages and increased numbers of effector T cells were shown to reestablish pulmonary immunity. Hence, LNP-mRNA treatment for fibrosis can restore pulmonary structure and function to similar degrees to those of a healthy lung. This therapy is a potential treatment for IPF patients. Pulmonary fibrosis is a severe lung disease with limited clinical therapies. Here the authors show that chimeric antigen receptor cells can rescue pulmonary fibrosis in a mouse model, and they further investigate the mechanism of lung regeneration after treatment.

Idiopathic pulmonary fibrosis (IPF) is a lung disease that worsens over time, causing fibrosis in the lungs and ultimately resulting in respiratory failure and a high risk of death. Macrophages play a crucial role in the immune system, showing flexibility by transforming into either pro-inflammatory (M1) or anti-inflammatory (M2) macrophages when exposed to different stimuli, ultimately impacting the development of IPF. Recent research has indicated that the polarization of macrophages is crucial in the onset and progression of IPF. M1 macrophages secrete inflammatory cytokines and agents causing early lung damage and fibrosis, while M2 macrophages support tissue healing and fibrosis by releasing anti-inflammatory cytokines. Developing novel treatments for IPF relies on a thorough comprehension of the processes involved in macrophage polarization in IPF. The review outlines the regulation of macrophage polarization and its impact on the development of IPF, with the goal of investigating the possible therapeutic benefits of macrophage polarization in the advancement of IPF.