Front Immunol. 2022 Jun 15;13:891448. doi: 10.3389/fimmu.2022.891448. eCollection 2022.

ABSTRACT

BACKGROUNDS: Growth differentiation factor 15 (GDF-15) is a highly divergent member of the TGF-β superfamily and has been implicated in various biological functions. However, the expression of GDF-15 in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is unclear.

METHOD: The study included 47 AE-IPF patients, 61 stable IPF (S-IPF) subjects, and 31 healthy controls (HCs). Serum GDF-15 levels and their expression in the lung were measured. The correlation between serum GDF-15 and other clinical parameters and the risk factors for AE occurrence and the survival of IPF patients were analyzed.

RESULTS: Serum GDF-15 levels were significantly elevated in AE-IPF patients (1279.22 ± 540.02 pg/ml) as compared with HCs (891.30 ± 479.90 pg/ml) or S-IPF subjects (107.82 ± 14.21 pg/ml) (both p < 0.001). The protein and mRNA expressions of GDF-15 in the lung of AE-IPF patients were significantly increased as compared with S-IPF cases (p = 0.007 and p = 0.026, respectively). The serum GDF-15 level was correlated with the clinical variables of inflammation, metabolism, and disease severity in IPF subjects (all p < 0.05). The GDF-15 serum concentration was significantly higher in decedents than in survivors (p = 0.005). A serum GDF-15 level above 989.3 pg/ml was a risk factor for AE occurrence (p = 0.04), and the level above 1,075.76 pg/ml was an independent predictor for survival in IPF cases (p = 0.007).

CONCLUSIONS: The GDF-15 level was significantly elevated in subjects with AE-IPF. GDF-15 could be a promising biomarker for AE occurrence and survival in IPF patients.

PMID:35784345 | PMC:PMC9241490 | DOI:10.3389/fimmu.2022.891448

Front Mol Med. 2022;2:842558. doi: 10.3389/fmmed.2022.842558. Epub 2022 Mar 15.

ABSTRACT

Idiopathic pulmonary fibrosis is a lethal disease driven by myofibroblast expansion. Currently no therapies exist that target the epigenetic mechanisms controlling myofibroblast transdifferentiation, which is responsible for unregulated extracellular matrix (ECM) production. We have recently shown that bromodomain-containing protein 4 (BRD4), an epigenetic regulator that forms a scaffold for nuclear activators and transcription factors, is essential for TGFβ-induced myofibroblast transdifferentiation. However, its role in the development and progression of pulmonary fibrosis in vivo has not been established. Here, we evaluate the hypothesis that BRD4 bromodomain interactions mediate myofibroblast expansion and fibrosing disease in vivo. C57BL/6J mice challenged with intratracheal bleomycin were systemically treated with a selective allosteric inhibitor of the BRD4 bromodomain 1 (BD1), ZL0591 (10 mg/kg), during the established fibrotic phase (14 days post-bleomycin) in a rigorous therapeutic paradigm. Eleven days after initiation of ZL0591 treatment (25 days post-bleomycin), we detected a significant improvement in blood O2 saturation compared to bleomycin/vehicle control. Twenty-eight days post-bleomycin, we observed a reduction in the volumetric Hounsfield Unit (HU) density by micro computed tomography (μCT) in the ZL0591-treated group, as well as a reduction in collagen deposition (hydroxyproline content) and severity of injury (Ashcroft scoring). Myofibroblast transdifferentiation was measured by smooth muscle α-actin (αSMA) staining, indicating a loss of this cell population in the ZL0591-treated group, and corresponded to reduced transcript levels of myofibroblast-associated extracellular matrix genes, tenascin-C and collagen 1α1. We conclude that BRD4 BD1 interactions are critical for myofibroblast transdifferentiation and fibrotic progression in a mouse model of pulmonary fibrosis.

PMID:35782526 | PMC:PMC9245900 | DOI:10.3389/fmmed.2022.842558

Asian J Pharm Sci. 2022 May;17(3):447-461. doi: 10.1016/j.ajps.2022.04.004. Epub 2022 Apr 30.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a serious and fatal pulmonary inflammatory disease with an increasing incidence worldwide. The drugs nintedanib and pirfenidone, are listed as conditionally recommended drugs in the "Evidence-Based Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis". However, these two drugs have many adverse reactions in clinical application. Salvianolic acid B (Sal B), a water-soluble component of Salvia miltiorrhiza, could alleviate bleomycin-induced peroxidative stress damage, and prevent or delay the onset of IPF by regulating inflammatory factors and fibrotic cytokines during the disease's progression. However, Sal B is poorly absorbed orally, and patient compliance is poor when administered intravenously. Therefore, there is an urgent need to find a new non-injection route of drug delivery. In this study, Sal B was used as model drug and l-leucine (LL) as excipient to prepare Sal B dry powder inhaler (Sal B-DPI) by spray drying method. Modern preparation evaluation methods were used to assess the quality of Sal B-DPI. Sal B-DPI is promising for the treatment of IPF, according to studies on pulmonary irritation evaluation, in vivo and in vitro pharmacodynamics, metabolomics, pharmacokinetics, and lung tissue distribution.

PMID:35782322 | PMC:PMC9237582 | DOI:10.1016/j.ajps.2022.04.004

Quant Imaging Med Surg. 2022 Jul;12(7):3655-3665. doi: 10.21037/qims-21-1232.

ABSTRACT

BACKGROUND: The quantitative analysis of high-resolution computed tomography (HRCT) is increasingly being used to quantify the severity and evaluate the prognosis of disease. Our aim was to quantify the HRCT features of idiopathic pulmonary fibrosis (IPF) and identify their association with pulmonary function tests.

METHODS: This was a retrospective, single-center, clinical research study. Patients with IPF were retrospectively included. Pulmonary segmentation was performed using the deep learning-based method. Radiologists manually segmented 4 findings of IPF, including honeycombing (HC), reticular pattern (RE), traction bronchiectasis (TRBR), and ground glass opacity (GGO). Pulmonary vessels were segmented with the automatic integration segmentation method. All segmentation results were quantified by the corresponding segmentation software. Correlations between the volume of the 4 findings on HRCT, volume of the lesions at different sites, pulmonary vascular-related parameters, and pulmonary function tests were analyzed.

RESULTS: A total of 101 IPF patients (93 males) with a median age of 63 years [interquartile range (IQR), 58 to 68 years] were included in this study. Total lesion extent demonstrated a stronger negative correlation with diffusion capacity for carbon monoxide (DLco) compared to HC, RE, and TRBR [total lesion ratio, correlation coefficient (r) =-0.67, P<0.001; HC, r=-0.45, P<0.001; RE, r=-0.41, P<0.001; TRBR, r=-0.25, P<0.05, respectively]. Correlations with lung function were similar among various lesion sites with r from -0.38 to -0.61 (P<0.001). Pulmonary artery volume (PAV) displayed a slightly increased positive association with the DLco compared to total pulmonary vascular volume (PVV); for PAV, r=0.41 and P<0.001 and for total PVV, r=0.36 and P<0.001. Additionally, total lesion extent, HC, and RE indicated a negative relationship with vascular-related parameters, and the strength of the correlations was independent of lesion site.

CONCLUSIONS: Quantitative analysis of HRCT features of IPF indicated a decline in function and an aggravation of vascular destruction with increasing lesion extent. Furthermore, a positive correlation between vascular-related parameters and pulmonary function was confirmed. This co-linearity indicated the potential of vascular-related parameters as new objective markers for evaluating the severity of IPF.

PMID:35782232 | PMC:PMC9246749 | DOI:10.21037/qims-21-1232

Adv Ther. 2022 Jul 3. doi: 10.1007/s12325-022-02229-8. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The targeting of fibroblasts and myofibroblasts with antifibrotic treatments is a potential therapeutic target for these potentially fatal diseases. Treprostinil is unique among the prostacyclin mimetics in that it has distinct actions at additional prostaglandin receptors. Preclinical and clinical evidence suggests that treprostinil has antifibrotic effects through the activation of the prostaglandin E receptor 2 (EP2), the prostaglandin D receptor 1 (DP1), and peroxisome proliferator-activated receptors (PPAR). In vivo studies of EP2 and the DP1 have found that administration of treprostinil resulted in a reduction in cell proliferation, reduced collagen secretion and synthesis, and reduced lung inflammation and fibrosis. In vitro and in vivo studies of PPARβ and PPARγ demonstrated that treprostinil inhibited fibroblast proliferation in a dose-dependent manner. Clinical data from a post hoc analysis of the INCREASE trial found that inhaled treprostinil improved forced vital capacity in the overall population as well as in idiopathic interstitial pneumonia and idiopathic pulmonary fibrosis subgroups. These preclinical and clinical findings suggest a dual benefit of treprostinil through the amelioration of both lung fibrosis and pulmonary hypertension.

PMID:35781186 | DOI:10.1007/s12325-022-02229-8

Sci Rep. 2022 Jul 1;12(1):11122. doi: 10.1038/s41598-022-15321-4.

ABSTRACT

Antibodies to Ro52/tripartite motif-containing 21 (TRIM21), referred to as anti-Ro52, are found in patients diagnosed with diverse systemic autoimmune rheumatic disease and associated with interstitial lung diseases. However, little is known about the clinical characteristics of anti-Ro52 in patients with idiopathic interstitial pneumonias (IIPs). We aimed to analyze the prevalence, co-existent autoantibodies, and clinical characteristics of anti-Ro52 in patients with IIP. The study enrolled 288 patients diagnosed with IIP. Clinical, laboratory and radiographic findings of IIP patients were compared between anti-Ro52 positives and negatives. Anti-Ro52 (20/288; 6.9%), anti-ARS (18/288; 6.3%), and anti-Ro60/SS-A (16/288; 5.6%) were the most common autoantibodies detected in IIP patients. Among 20 IIP patients who had anti-Ro52, anti-ARS was present in 8 (40%) patients. The criteria for interstitial pneumonia with autoimmune features (IPAF) were significantly better fulfilled by patients with anti-Ro52 than those without (P = 0.001). Meeting serological domain (P < 0.001) and Raynaud's phenomenon (P = 0.009) were significantly more common in the anti-Ro52-positive patients. Anti-Ro52-positive IIP patients have clinical features consistent with IPAF. Anti-Ro52 may have an important role in detecting the autoimmune phenotype in IIP patients.

PMID:35778430 | PMC:PMC9249750 | DOI:10.1038/s41598-022-15321-4

Pathology. 2022 Jun 29:S0031-3025(22)00173-8. doi: 10.1016/j.pathol.2022.05.002. Online ahead of print.

ABSTRACT

The pathogenesis of idiopathic pulmonary fibrosis (IPF) and its histological counterpart, usual interstitial pneumonia (UIP) remains debated. IPF/UIP is a disease characterised by respiratory restriction, and while there have been recent advances in treatment, mortality remains high. Genetic and environmental factors predispose to its development and aberrant alveolar repair is thought to be central. Following alveolar injury, the type II pneumocyte (AEC2) replaces the damaged thin type I pneumocytes. Despite the interstitial fibroblast being considered instrumental in formation of the fibrosis, there has been little consideration for a role for AEC2 in the repair of the septal interstitium. Elastin is a complex protein that conveys flexibility and recoil to the lung. The fibroblast is presumed to produce elastin but there is evidence that the AEC2 may have a role in production or deposition. While the lung is an elastic organ, the role of elastin in repair of lung injury and its possible role in UIP has not been explored in depth. In this paper, pathogenetic mechanisms of UIP involving AEC2 and elastin are reviewed and the possible role of AEC2 in elastin generation is proposed.

PMID:35778287 | DOI:10.1016/j.pathol.2022.05.002

Thorax. 2022 Jul 1:thoraxjnl-2021-218315. doi: 10.1136/thoraxjnl-2021-218315. Online ahead of print.

ABSTRACT

BACKGROUND: Interstitial lung abnormalities (ILAs) are associated with increased mortality. It is unclear whether multimorbidity accounts for the mortality association or how strongly ILA is associated with mortality relative to other common age-associated diseases. We determined the association of ILA with all-cause mortality adjusted for multimorbidity, compared mortality associated with ILA and prevalent cardiovascular disease (CVD), diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease and cancer and also determined the association between ILA and these diseases.

METHODS: We measured ILA (none, indeterminant, definite) using blinded reads of CT images, prevalent chronic diseases and potential confounders in two observational cohorts, the Framingham Heart Study (FHS) (n=2449) and Age, Gene/Environment Susceptibility - Reykjavik Study (AGES-Reykjavik) (n=5180). We determined associations with mortality using Cox proportional hazards models and between ILA and diseases with multinomial logistic regression.

RESULTS: Over a median (IQR) follow-up of 8.8 (1.4) years in FHS and 12.0 (7.7) years in AGES-Reykjavik, in adjusted models, ILAs were significantly associated with increased mortality (HR, 95% CI 1.95, 1.23 to 3.08, p=0.0042, in FHS; HR 1.60, 1.41 to 1.82, p<0.0001, in AGES-Reykjavik) adjusted for multimorbidity. In both cohorts, the association of ILA with mortality was of similar magnitude to the association of most other diseases. In adjusted models, ILAs were associated only with prevalent kidney disease (OR, 95% CI 1.90, 1.01 to 3.57, p=0.0452) in FHS and with prevalent CVD (OR 1.42, 1.12 to 1.81, p=0.0040) in AGES-Reykjavik.

CONCLUSIONS: ILAs were associated with mortality adjusted for multimorbidity and were similarly associated with increased mortality compared with several common chronic diseases. ILAs were not consistently associated with the prevalence of these diseases themselves.

PMID:35777957 | DOI:10.1136/thoraxjnl-2021-218315

Eur Respir J. 2022 Jul 1:2102307. doi: 10.1183/13993003.02307-2021. Online ahead of print.

ABSTRACT

Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to their differentiation into myofibroblasts, thereby promoting the development of lung fibrosis. Bone morphogenetic protein 4 (BMP4), a multifunctional growth factor, is essential for the early stage of lung development, however, the role of BMP4 in modulating lung fibrosis remains unknown.This study was to evaluate the role of BMP4 in lung fibrosis using BMP4-haplodeleted mice, BMP4-overexpressed mice, primary lung fibroblasts, and lung samples from patients with IPF.BMP4 expression was down-regulated in IPF lungs and fibroblasts compared to control individuals, negatively correlated with fibrotic genes, and BMP4 decreased with TGF-β1 stimulation in lung fibroblasts in a time- and dose-dependent manner. In mice challenged with bleomycin, BMP4 haploinsufficiency perpetuated activation of lung myofibroblasts and caused accelerated lung function decline, severe fibrosis and mortality. While BMP4 overexpression using AAV9 vectors showed preventative and therapeutic efficacy against lung fibrosis. In vitro, BMP4 attenuated TGF-β1-induced fibroblast-to-myofibroblast differentiation and extracellular matrix (ECM) production by reducing impaired mitophagy and cellular senescence in lung fibroblasts. Whereas Pink1 silencing by shRNA transfection abolished the ability of BMP4 to reverse the TGF-β1-induced myofibroblast differentiation and ECM production, indicating dependence on Pink1-mediated mitophagy. Moreover, the inhibitory effect of BMP4 on fibroblast activation and differentiation was accompanied with an activation of Smad1/5/9 signaling and suppression of TGF-β1-meidtaed Smad2/3 signaling in vivo and in vitroIn conclusion, strategies for enhancing BMP4 signaling may represent an effective treatment for pulmonary fibrosis.

PMID:35777761 | DOI:10.1183/13993003.02307-2021

Ann Am Thorac Soc. 2022 Jul;19(7):1095-1097. doi: 10.1513/AnnalsATS.202203-276ED.

NO ABSTRACT

PMID:35772099 | DOI:10.1513/AnnalsATS.202203-276ED

Sci Rep. 2022 Jun 30;12(1):11086. doi: 10.1038/s41598-022-14832-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form of interstitial lung disease. IPF is characterized by irreversible scarring of the lungs leading to lung function decline. Although the etiology remains poorly understood, dysregulated autophagy in alveolar-epithelial cells (AECs) together with interplay between apoptotic-AECs and proliferative-myofibroblasts have been strongly implicated in IPF pathogenesis. Recent studies have revealed that a caveolin-1-derived 7-mer peptide, CSP7, mitigates established PF at least in part by improving AEC viability. In the present study, we aimed to determine whether and how CSP7 regulates autophagy in fibrotic-lung AECs. We found that p53 and autophagic proteins were markedly upregulated in AECs from mice with single/multi-doses of bleomycin-or silica-induced PF. This was abolished following treatment of PF-mice with CSP7. Further, CSP7 abrogated silica- or bleomycin-induced p53 and autophagy proteins in AECs. Immunoprecipitation further revealed that CSP7 abolishes the interaction of caveolin-1 with LC3BII and p62 in AECs. AEC-specific p53-knockout mice resisted silica- or bleomycin-induced changes in autophagy proteins, or CSP7 treatment. Our findings provide a novel mechanism by which CSP7 inhibits dysregulated autophagy in injured AECs and mitigates existing PF. These results affirm the potential of CSP7 for treating established PF, including IPF and silicosis.

PMID:35773303 | DOI:10.1038/s41598-022-14832-4

Signal Transduct Target Ther. 2022 Jun 30;7(1):206. doi: 10.1038/s41392-022-01070-3.

ABSTRACT

Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop fibrosis, including the liver, kidney, heart, and lung. Fibrosis such as liver cirrhosis, idiopathic pulmonary fibrosis, and cystic fibrosis caused substantial disease burden. Persistent abnormal activation of myofibroblasts mediated by various signals, such as transforming growth factor, platelet-derived growth factor, and fibroblast growh factor, has been recongized as a major event in the occurrence and progression of fibrosis. Although the mechanisms driving organ-specific fibrosis have not been fully elucidated, drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials. In this review, we briefly introduce the aetiology and epidemiology of several fibrosis diseases, including liver fibrosis, kidney fibrosis, cardiac fibrosis, and pulmonary fibrosis. Then, we summarise the abnormal cells (epithelial cells, endothelial cells, immune cells, and fibroblasts) and their interactions in fibrosis. In addition, we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation, extracellular matrix cross-linking, metabolism, and inflammation in fibrosis. Finally, we discuss the anti-fibrotic drugs based on their targets and clinical trials. This review provides reference for further research on fibrosis mechanism, drug development, and clinical trials.

PMID:35773269 | DOI:10.1038/s41392-022-01070-3

Clin Res Hepatol Gastroenterol. 2022 Jun 27:101977. doi: 10.1016/j.clinre.2022.101977. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Cystic fibrosis liver disease (CFLD) is the third leading cause of death in patients with cystic fibrosis (CF). We aim to determine the prevalence of CFLD in a cohort of adult patients with CF and to characterise liver involvement in this population highlighting the importance of histological diagnosis.

METHODS: We retrospectively studied a cohort of patients with CF. Inclusion criteria were age ≥ 18 and minimum 1 year of follow-up. We excluded lung transplant patients. CFLD was defined as having 2 out of 3 criteria: persistent elevation of transaminases and/or gamma-glutamyltransferase; abnormal ultrasound; and abnormal transient elastography. Non-invasive fibrosis biomarkers were calculated in CFLD patients. Adult-onset CFLD (Ad-CFLD) was defined as CFLD ≥18 years. Severe CFLD (s-CFLD) was defined as CFLD with cirrhosis and/or portal hypertension.

RESULTS: We included 113 patients. Median age was 29 years, 58 were male. Forty patients had CFLD. Median age at CFLD diagnosis was 10 years. Twenty-one patients had s-CFLD. Two s-CFLD patients had nodular regenerative hyperplasia, 1 had hepatocellular carcinoma and 4 underwent liver transplantation. Six patients had ad-CFLD. Both CFLD and s-CFLD groups were compared to a non-CFLD group. The CFLD group had significantly more males (p=0.034). S-CFLD group had worse pulmonary function (p=0.015).

CONCLUSION: Thirty five percent of adult patients with CF, mainly males, had CFLD. Nineteen percent had s-CFLD and had worse pulmonary function. With recent reports unravelling different pathophysiological mechanisms in CFLD, we believe it is important to better characterise liver involvement using liver biopsy.

PMID:35772685 | DOI:10.1016/j.clinre.2022.101977

Am J Respir Crit Care Med. 2022 Jun 30. doi: 10.1164/rccm.202112-2824OC. Online ahead of print.

ABSTRACT

RATIONALE: Treatment options for idiopathic pulmonary fibrosis (IPF) are limited.

OBJECTIVES: To evaluate the efficacy and safety of BG00011, an anti-αvβ6 IgG1 monoclonal antibody, in the treatment of patients with IPF.

METHODS: In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (forced vital capacity [FVC] ≥50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo. Primary endpoint was FVC change from baseline at Week 52. Due to early trial termination (imbalance in adverse events [AEs] and lack of clinical benefit), endpoints were evaluated at Week 26 as an exploratory analysis.

MEASUREMENTS AND MAIN RESULTS: 106 patients were randomized and received ≥1 dose of BG00011 (n = 54) or placebo (n = 52). At Week 26, there was no significant difference in FVC change from baseline (SE) between patients who received BG00011 (n = 20) or placebo (n = 23), -0.056 L (0.0593) vs. -0.097 L (0.0600), respectively; P=0.268. However, after Week 26, patients in the BG00011 group showed a worsening trend. Eight of 18 (44.4%) who received BG00011 and 4 of 22 (18.2%) who received placebo showed worsening of fibrosis on high-resolution computed tomography at end of treatment. IPF exacerbation/or progression was reported in 13 patients (all in the BG00011 group). Serious AEs occurred more frequently in BG00011 patients, including four deaths.

CONCLUSIONS: The results do not support the continued clinical development of BG00011. Further research is warranted to identify new treatment strategies that modify inflammatory and fibrotic pathways in IPF Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT03573505.

PMID:35771569 | DOI:10.1164/rccm.202112-2824OC

Am J Respir Crit Care Med. 2022 Jun 30. doi: 10.1164/rccm.202109-2166OC. Online ahead of print.

ABSTRACT

RATIONALE: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in SARS-CoV-2 infection and disease severity is unclear.

OBJECTIVES: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP).

METHODS: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by trans-ancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (BMI, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects.

MEASUREMENTS AND MAIN RESULTS: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations (Ncases=4,325/, Ncontrols=507,640; OR=0.89 [0.82-0.97], p=6.86 x 10-03) in trans-ancestry meta-analysis within MVP and joint meta-analyses with the HGI (Ncases=13,320, Ncontrols=1,508,841; OR=0.90 [0.86-0.95], p =8.99 x 10-05). The rs35705950-T allele was not associated reduced COVID-19 positivity in trans-ancestry meta-analysis within MVP (Ncases=19,168/Ncontrols=492,854; OR=0.98 [0.95-1.01], p=0.06) but was nominally significant (p<0.05) in the joint meta-analysis with HGI (Ncases=44,820/Ncontrols=1,775,827; OR=0.97 [0.95-1]; p=0.03). We did not observe associations with severe outcomes or mortality. Among MVP individuals of European ancestry, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR=0.82 [0.72-0.93], p=0.001).

CONCLUSIONS: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:35771531 | DOI:10.1164/rccm.202109-2166OC

Front Immunol. 2022 Jun 13;13:705472. doi: 10.3389/fimmu.2022.705472. eCollection 2022.

ABSTRACT

Extracellular vesicles (EVs) can regulate the polarization of macrophages in a variety of inflammatory diseases by mediating intercellular signal transduction and affecting the occurrence and development of diseases. After macrophages are regulated by EVs, they mainly show two phenotypes: the proinflammatory M1 type and the anti-inflammatory M2 type. A large number of studies have shown that in diseases such as mastitis, inflammatory bowel disease, Acute lung injury, and idiopathic pulmonary fibrosis, EVs promote the progression of the disease by inducing the M1-like polarization of macrophages. In diseases such as liver injury, asthma, and myocardial infarction, EVs can induce M2-like polarization of macrophages, inhibit the inflammatory response, and reduce the severity of the disease, thus indicating new pathways for treating inflammatory diseases. The EV/macrophage axis has become a potential target for inflammatory disease pathogenesis and comprehensive treatment. This article reviews the structure and function of the EV/macrophage axis and summarizes its biological functions in inflammatory diseases to provide insights for the diagnosis and treatment of inflammatory diseases.

PMID:35769456 | PMC:PMC9234271 | DOI:10.3389/fimmu.2022.705472

Ann Agric Environ Med. 2022 Jun 24;29(2):306-308. doi: 10.26444/aaem/148049. Epub 2022 May 6.

ABSTRACT

INTRODUCTION AND OBJECTIVE: Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by iterative inhalation of various environmental agents. The clinical presentation is variable, acute HP commonly presents an inflammatory response, whereas the development and clinical consequences in chronic HP may be similar to IPF (idiopathic pulmonary fibrosis). The aim of the study is to present the latest discoveries regarding the genetic predisposition of HP.

MATERIAL AND METHODS: The appropriate scientific literature was reviewed and analyzed.

RESULTS: Studies have discovered relevant gene polymorphisms in HP, including polymorphisms in the major histocompatibility complex in the metalloproteinases genes. The length of the peripheral blood leukocyte telomere has been investigated and discovered to be important. Recently, the need to study miRNAs in ILD (interstitial lung disease) has been highlighted.

CONCLUSIONS: Exposed HP developed only in some people and a genetic susceptibility significantly increases the risk. Further more current studies on large groups of patients are needed to learn more about the genetic predisposition and risk factors of HP.

PMID:35767769 | DOI:10.26444/aaem/148049

Med Sci (Paris). 2022 Jun-Jul;38(6-7):579-584. doi: 10.1051/medsci/2022084. Epub 2022 Jun 29.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal lung disease of unknown origin. It is characterized by aberrant scarring of the alveolar epithelium leading to an accumulation of extracellular matrix (ECM). Fibroblastic foci, consisting of fibroblasts and myofibroblasts, are responsible for the excessive production of ECM. The two therapeutic molecules available on the market to date only allow to slow down the evolution of the disease. In this review, we present the mechanisms involved in the progression of the disease, its treatments and the study models.

PMID:35766856 | DOI:10.1051/medsci/2022084

Compr Physiol. 2022 Jun 29;12(3):3509-3522. doi: 10.1002/cphy.c210026.

ABSTRACT

The lungs are continually subjected to noxious and inert substances, are immunologically active, and are in a constant state of damage and repair. This makes the pulmonary system particularly vulnerable to diseases of aging. Aging can be understood as random molecular damage that is unrepaired and accumulates over time, resulting in cellular defects and tissue dysfunction. The breakdown of cellular mechanisms, including stem cell exhaustion, genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, altered intercellular communication, and changes in the extracellular matrix is thought to advance the aging process itself. Chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cancers illustrate a pathologic breakdown in these mechanisms beyond normal aging. The immune system becomes less effective with advancing age. There is a low-level state of chronic inflammation termed inflammaging which is thought to be driven by immunosenescence, the changes in the innate and adaptive immune systems with advancing age that lead to dysregulation and decreased effectiveness of the immune system. These processes of aging lead to expected changes in the form and function of the respiratory system, most notably a loss of lung elasticity, decrease in respiratory muscle strength, increase in ventilation-perfusion mismatching, and stiffening of the vasculature. The astute clinician is aware of these expected findings and does not often attribute dyspnea to aging alone. Maintaining a low threshold to investigate for comorbid disease and understanding how pulmonary disease presents differently in the elderly than in younger adults can improve clinical outcomes. © 2022 American Physiological Society. Compr Physiol 12:3509-3522, 2022.

PMID:35766832 | DOI:10.1002/cphy.c210026

Stem Cell Res Ther. 2022 Jun 28;13(1):279. doi: 10.1186/s13287-022-02966-1.

ABSTRACT

BACKGROUND: As a fatal interstitial lung disease, idiopathic pulmonary fibrosis (IPF) was characterized by the insidious proliferation of extracellular matrix (ECM)-producing mesenchymal cells. Recent studies have demonstrated that lung resident mesenchymal/stromal cells (LR-MSC) are the source of myofibroblasts. Endoplasmic reticulum (ER) stress is prominent in IPF lung. This study sought to investigate the effects of ER stress on the behavior of LR-MSC during pulmonary fibrosis.

METHODS: ER stress and myofibroblast differentiation of LR-MSC in patients with IPF were evaluated. Primary mouse LR-MSC was harvested and used in vitro for testing the effects of ER stress and C/EBP homologous protein (CHOP) on LR-MSC. Adoptive transplantation of LR-MSC to bleomycin-induced pulmonary fibrosis was done to test the in vivo behavior of LR-MSC and its influence on pulmonary fibrosis.

RESULTS: We found that myofibroblast differentiation of LR-MSC is associated with ER stress in IPF and bleomycin-induced mouse fibrotic lung. Tunicamycin-induced ER stress impairs the paracrine, migration, and reparative function of mouse LR-MSC to injured type 2 alveolar epithelial cells MLE-12. Overexpression of the ER stress responder C/EBP homologous protein (CHOP) facilitates the TGFβ1-induced myofibroblast transformation of LR-MSC via boosting the TGFβ/SMAD signaling pathway. CHOP knockdown facilitates engraftment and inhibits the myofibroblast transformation of LR-MSC during bleomycin-induced pulmonary fibrosis, thus promoting the efficacy of adopted LR-MSC in alleviating pulmonary fibrosis.

CONCLUSION: Our work revealed a novel role that ER stress involved in pulmonary fibrosis by influencing the fate of LR-MSC and transformed to "crime factor" myofibroblast, during which CHOP acts as the key modulator. These results indicate that pharmacies targeting CHOP or therapies based on CHOP knockdown LR-MSC may be promising ways to treat pulmonary fibrosis.

PMID:35765096 | DOI:10.1186/s13287-022-02966-1