Respir Res. 2022 Jan 6;23(1):2. doi: 10.1186/s12931-021-01907-5.

NO ABSTRACT

PMID:34991577 | DOI:10.1186/s12931-021-01907-5

PLoS One. 2022 Jan 6;17(1):e0262082. doi: 10.1371/journal.pone.0262082. eCollection 2022.

ABSTRACT

BACKGROUND: The lower airways microbiome and host immune response in chronic pulmonary diseases are incompletely understood. We aimed to investigate possible microbiome characteristics and key antimicrobial peptides and proteins in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

METHODS: 12 IPF patients, 12 COPD patients and 12 healthy controls were sampled with oral wash (OW), protected bronchoalveolar lavage (PBAL) and right lung protected sterile brushings (rPSB). The antimicrobial peptides and proteins (AMPs), secretory leucocyte protease inhibitor (SLPI) and human beta defensins 1 and 2 (hBD-1 & hBD-2), were measured in PBAL by enzyme linked immunosorbent assay (ELISA). The V3V4 region of the bacterial 16S rDNA gene was sequenced. Bioinformatic analyses were performed with QIIME 2.

RESULTS: hBD-1 levels in PBAL for IPF were lower compared with COPD. The predominant phyla in IPF were Firmicutes, Bacteroides and Actinobacteria; Proteobacteria were among top three in COPD. Differential abundance analysis at genus level showed significant differences between study groups for less abundant, mostly oropharyngeal, microbes. Alpha diversity was lower in IPF in PBAL compared to COPD (p = 0.03) and controls (p = 0.01), as well as in rPSB compared to COPD (p = 0.02) and controls (p = 0.04). Phylogenetic beta diversity showed significantly more similarity for IPF compared with COPD and controls. There were no significant correlations between alpha diversity and AMPs.

CONCLUSIONS: IPF differed in microbial diversity from COPD and controls, accompanied by differences in antimicrobial peptides. Beta diversity similarity between OW and PBAL in IPF may indicate that microaspiration contributes to changes in its microbiome.

PMID:34990493 | DOI:10.1371/journal.pone.0262082

JCI Insight. 2022 Jan 6:e152690. doi: 10.1172/jci.insight.152690. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by collagen deposition within the lung interstitium. Bacterial infection is associated with increased morbidity and more rapid mortality in IPF patient populations and pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are commonly isolated from the lungs of hospitalized IPF patients. Despite this, the effects of fibrotic lung injury on critical immune responses to infection remain unknown. In the present study, we show that, like human IPF, fibrotic mice infected with MRSA exhibit increased morbidity and mortality compared to uninfected fibrotic mice. We determine that fibrosis confers a defect in MRSA clearance compared to non-fibrotic mice, resulting from blunted innate immune responses. We show that fibrosis inhibits neutrophil intracellular killing of MRSA through impaired neutrophil elastase (NE) release and oxidative radical production. Additionally, we demonstrate that lung macrophages from fibrotic mice have impaired phagocytosis of MRSA. Our study describes potentially novel impairments to antimicrobial responses upon the development of pulmonary fibrosis and our findings suggest a possible mechanism for why IPF patients are at greater risk of morbidity and mortality related to infection.

PMID:34990413 | DOI:10.1172/jci.insight.152690

Am J Physiol Lung Cell Mol Physiol. 2022 Jan 5. doi: 10.1152/ajplung.00251.2021. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease. The pathogenesis of IPF is not completely understood. However, numerous genes are associated with the development and progression of pulmonary fibrosis, indicating there is a significant genetic component to the pathogenesis of IPF. Epigenetic influences on the development of human disease, including pulmonary fibrosis, remain to be fully elucidated. In this paper we identify miR-338-3p as a microRNA severely downregulated in the lungs of patients with pulmonary fibrosis and in experimental models of pulmonary fibrosis. Treatment of primary human lung fibroblasts with miR-338-3p inhibits myofibroblast differentiation and matrix protein production. Published and proposed targets of miR-338-3p such as TGFβ receptor 1, MEK/ERK 1/2, Cdk4 and Cyclin D are also not responsible for the regulation of pulmonary fibroblast behavior by miR-338-3p. miR-338-3p inhibits myofibroblast differentiation by preventing TGFβ-mediated downregulation of phosphatase and tensin homolog (PTEN), a known anti-fibrotic mediator.

PMID:34986654 | DOI:10.1152/ajplung.00251.2021

Am J Respir Crit Care Med. 2022 Jan 5. doi: 10.1164/rccm.202010-3880OC. Online ahead of print.

ABSTRACT

Rationale: The Toll-like receptor 3 Leu412Phe (TLR3 L412F) polymorphism attenuates cellular anti-viral responses and is associated with accelerated disease progression in IPF. The role of TLR3 L412F in bacterial infection in IPF or in acute exacerbations (AE) has not been reported. Objective: To characterize the association between TLR3 L412F and AE-related death in IPF. To determine the effect of TLR3 L412F on the lung microbiome and on anti-bacterial TLR-responses of primary lung fibroblasts from IPF patients. Methods: TLR-mediated anti-bacterial and anti-viral responses were quantitated in L412F-wild-type and 412F-heterozygous primary lung fibroblasts from IPF patients using ELISA, western blot analysis and qPCR. Hierarchical heatmap analysis was employed to establish bacterial and viral clustering in nasopharyngeal lavage (NPL) samples from AE-IPF patients. 16S rRNA qPCR and pyrosequencing were used to determine the effect of TLR3 L412F on the IPF lung microbiome. Measurements and Main Results: A significant increase in AE-related death in 412F-variant IPF patients was reported. We established that 412F-heterozygous IPF lung fibroblasts have reduced anti-bacterial TLR responses to LPS (TLR4), Pam3CYSK4 (TLR1/2), flagellin (TLR5) and FSL-1 (TLR6/1) and have reduced responses to live Pseudomonas aeruginosa infection. Using 16S rRNA sequencing, we demonstrated that 412F-heterozygous IPF patients have a dysregulated lung microbiome with increased frequencies of Streptococcus and Staphylococcus spp. Conclusions: This study reveals that TLR3 L412F dysregulates the IPF lung microbiome and reduces the responses of IPF lung fibroblasts to bacterial TLR-agonists and live bacterial infection. These findings identify a candidate role for TLR3 L412F in viral- and bacterial-mediated AE-death.

PMID:34985402 | DOI:10.1164/rccm.202010-3880OC

Am J Physiol Lung Cell Mol Physiol. 2022 Jan 5. doi: 10.1152/ajplung.00593.2020. Online ahead of print.

ABSTRACT

Increased senescence and expression of pro-fibrotic genes in old lung fibroblasts contribute to disrepair responses. We reported that primary lung fibroblasts from old mice have lower expression and activity of the cystine transporter Slc7a11/xCT than cells from young mice, resulting in changes in both the intracellular and extracellular redox environments. This study examines the hypothesis that low Slc7a11 expression in old lung fibroblasts promotes senescence and pro-fibrotic gene expression. The levels of mRNA and protein of Slc7a11, senescence markers, and pro-fibrotic genes were measured in primary fibroblasts from the lungs of old (24 months) and young (3 months) mice. In addition, the effects of genetic and pharmacological manipulation of Slc7a11 were investigated. We found that decreased expression of Slc7a11 in old cells was associated with elevated markers of senescence (p21, p16, p53 and b-galactosidase) and increased expression of pro-fibrotic genes (Tgfb1, Smad3, Acta2, Fn1, Col1a1 and Col5a1). Silencing of Slc7a11 in young cells replicated the aging phenotype, whereas overexpression of Slc7a11 in old cells decreased expression of senescence and pro-fibrotic genes. Young cells were induced to express the senescence and pro-fibrotic phenotype by sulfasalazine, an Slc7a11 inhibitor, whereas treatment of old cells with sulforaphane, an Slc7a11 inducer, decreased senescence without affecting pro-fibrotic genes. Like aging cells, idiopathic pulmonary fibrosis fibroblasts show decreased Slc7a11 expression and increased pro-fibrotic markers. In short, old lung fibroblasts manifest a pro-fibrotic and senescence phenotype that is modulated by genetic or pharmacological manipulation of Slc7a11.

PMID:34984918 | DOI:10.1152/ajplung.00593.2020

BMC Pulm Med. 2022 Jan 5;22(1):15. doi: 10.1186/s12890-021-01799-7.

ABSTRACT

BACKGROUND: With the rapid advances of genetic and genomic technologies, the pathophysiological mechanisms of idiopathic pulmonary fibrosis (IPF) were gradually becoming clear, however, the prognosis of IPF was still poor. This study aimed to systematically explore the ferroptosis-related genes model associated with prognosis in IPF patients.

METHODS: Datasets were collected from the Gene Expression Omnibus (GEO). The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to create a multi-gene predicted model from patients with IPF in the Freiburg cohort of the GSE70866 dataset. The Siena cohort and the Leuven cohort were used for validation.

RESULTS: Nineteen differentially expressed genes (DEGs) between the patients with IPF and control were associated with poor prognosis based on the univariate Cox regression analysis (all P < 0.05). According to the median value of the risk score derived from an 8-ferroptosis-related genes signature, the three cohorts' patients were stratified into two risk groups. Prognosis of high-risk group (high risk score) was significantly poorer compared with low-risk group in the three cohorts. According to multivariate Cox regression analyses, the risk score was an independently predictor for poor prognosis in the three cohorts. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) confirmed the signature's predictive value in the three cohorts. According to functional analysis, inflammation- and immune-related pathways and biological process could participate in the progression of IPF.

CONCLUSIONS: These results imply that the 8-ferroptosis-related genes signature in the bronchoalveolar lavage samples might be an effective model to predict the poor prognosis of IPF.

PMID:34983465 | DOI:10.1186/s12890-021-01799-7

Respirology. 2022 Jan 3. doi: 10.1111/resp.14195. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations.

METHODS: We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network.

RESULTS: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N-acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range -363 to -148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation.

CONCLUSION: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed.

PMID:34981600 | DOI:10.1111/resp.14195

J Med Case Rep. 2022 Jan 3;16(1):2. doi: 10.1186/s13256-021-03191-9.

ABSTRACT

BACKGROUND: In patients receiving single lung transplantation for idiopathic pulmonary fibrosis, worsening of fibrosis of the native lung is usually progressive over time, with no significant effects on gas exchange.

CASE PRESENTATION: Here, we describe the cases of two Caucasian male recipients of single lung transplants for idiopathic pulmonary fibrosis, 65 and 62 years of age, who exhibited acute worsening of lung fibrosis after an episode of serious viral infection (cytomegalovirus primo-infection in one case and COVID-19 in the other). In both cases, along with opacification of the native lung over several days, the patients presented acute respiratory failure that required the use of high-flow nasal oxygen therapy. Eventually, hypoxemic respiratory failure resolved, but with rapid progression of fibrosis of the native lung.

CONCLUSION: We conclude that acute worsening of fibrosis on the native lung secondary to a severe viral infection should be added to the list of potential complications developing on the native lung after single lung transplantation for idiopathic pulmonary fibrosis.

PMID:34980231 | DOI:10.1186/s13256-021-03191-9

Toxicol Appl Pharmacol. 2021 Dec 31:115856. doi: 10.1016/j.taap.2021.115856. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary fibrosis is a sequela of many pulmonary diseases, such as pneumoconiosis and idiopathic pulmonary fibrosis. The principal characteristics of pulmonary fibrosis comprise myofibroblast proliferation, alveolar damage and deposition of extracellular matrix components, which cause abnormal lung structure remodeling and an irreversible decline in lung function; however, the detailed mechanisms remain unclear. The current study focused on the role of ZC3H4, a new member of the zinc finger protein family, in SiO2-induced pulmonary fibrosis.

METHODS: The expression of ZC3H4 and fibroblast activation markers (COL1A1, COL3A1 and ACTA1) was measured by western blotting and immunofluorescence staining after SiO2 exposure (50 μg/cm2). The functional change in fibroblasts was studied with a scratch assay and a 3D migration assay. The CRISPR/Cas9 system was used to explore the regulatory mechanisms of ZC3H4 in pulmonary fibroblast cells.

RESULTS: The expression levels of ZC3H4 and sigmar1 (a key regulator of ER stress) were increased in pulmonary fibroblast cells and were associated with fibroblast activation, as indicated by the increase in COL1A1, COL3A1 and ACTA1, as well as the migration ability. SiO2-enhanced fibroblast activation was attenuated by specific knockdown of ZC3H4 and inhibition of ER stress, demonstrating that ZC3H4 activated fibroblasts via the sigmar1/ER stress pathway. Interestingly, ER stress blockade also inhibited ZC3H4 expression, indicating the positive feedback regulatory mechanism of ER stress on ZC3H4.

CONCLUSIONS: Our results demonstrate that ZC3H4 and sigmar1 might act as novel therapeutic targets for silicosis, providing a reference for further pulmonary fibrosis research.

PMID:34979141 | DOI:10.1016/j.taap.2021.115856

Biochem Biophys Rep. 2021 Dec 14;28:101186. doi: 10.1016/j.bbrep.2021.101186. eCollection 2021 Dec.

ABSTRACT

Despite years of positive animal data, hepatocyte growth factor (HGF) has never been developed into a useful pharmaceutical, primarily due to its poor pharmacological properties. CM1021 is a fusion protein containing the K1 loop of HGF and the human IgG1 Fc region. The experiments described here demonstrate that CM1021 has the biological properties of HGF and the pharmacological properties of a monoclonal antibody. CM1021 stimulates scattering and branching morphogenesis in MDCK cells and stimulates liver growth in vivo. Unlike HGF, it is available via intraperitoneal injection and has an estimated half-life similar to an antibody.

PMID:34977363 | PMC:PMC8683692 | DOI:10.1016/j.bbrep.2021.101186

Theranostics. 2022 Jan 1;12(2):747-766. doi: 10.7150/thno.65828. eCollection 2022.

ABSTRACT

Background: Immune checkpoint inhibitors (ICIs), such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have been widely applied in clinical and scientific research. Despite their effective antitumor effects in clinical tumor therapy, most tumors are still resistant to ICIs and long-term benefits are lacking. In addition, tumor patients complicated with interstitial lung disease limit the application of ICI therapy. Therefore, for these cases, there is an urgent need to develop new methods to relieve lung complications and enhance the efficacy of ICI therapy. Nintedanib, a potent triple angiokinase inhibitor approved for the treatment of progressive fibrotic interstitial lung disease. However, its immunotherapy synergy properties and mechanism are still pending further exploration. Methods: To explore the therapeutic potential of nintedanib and αPD-L1 combination therapy, MC38, LLC, and 4T1 tumor models were used to investigate antitumor and antimetastatic activities in vivo. An idiopathic pulmonary fibrosis-tumor bearing model was used to evaluate the effect of the synergy therapy on tumor model complicated with lung disease. Moreover, RNA-seq, immunohistochemistry, and flow cytometry were utilized to analyze the effect of combination treatment on the tumor microenvironment. The bioactivity following different treatments was determined by western blotting, CCK-8, and flow cytometry. Results: In this study, nintedanib and αPD-L1 synergy therapy exhibited significant antitumor, antimetastatic and anti-pulmonary fibrosis effects. Both in vitro and in vivo experiments revealed that these effects included promoting vessel normalization, increasing infiltration and activation of immune cells in tumors, enhancing the response of interferon-gamma, and activating the MHC class I-mediated antigen presentation process. Moreover, our results showed an increased expression of PD-L1 and promoted phosphorylation of STAT3 after nintedanib (1 µM) treatment. Conclusion: The combination of nintedanib and αPD-L1 increased ICI therapy responses, relieved lung complications and further activated the tumor immune microenvironment; thus, exhibiting a notable antitumor effect. Accordingly, the nintedanib synergy strategy is expected to be a promising candidate therapy for tumor patients complicated with interstitial lung disease in clinical practice.

PMID:34976211 | PMC:PMC8692903 | DOI:10.7150/thno.65828

Theranostics. 2022 Jan 1;12(2):530-541. doi: 10.7150/thno.62760. eCollection 2022.

ABSTRACT

Histone H4 lysine16 acetylation (H4K16Ac) modulates chromatin structure by serving as a switch from a repressive to a transcriptionally active state. This euchromatin mark is associated with active transcription. In this study, we investigated the effects of H4K16Ac on the expression of pro-fibrotic genes in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and in an aging murine model of lung fibrosis. Methods: The lung tissues and fibroblasts from human IPF/non-IPF donors and from aged mice with/without bleomycin induced lung fibrosis were used in this study. The H4K16Ac levels were examined by immunohistochemistry or western blots. RNA silencing of H4K16Ac acetyltransferase Mof was used to reduce H4K16Ac levels in IPF fibroblasts. The effects of reduced H4K16Ac on pro-fibrotic gene expression were examined by western blots and real-time PCR. The association of H4K16Ac with these genes' promoter region were evaluated by ChIP assays. The gene expression profile in siRNA Mof transfected IPF cells were determined by RNA-Seq. The impact of H4K16Ac levels on lung fibrosis was evaluated in an aging murine model. Results: Aged mice with bleomycin induced lung fibrosis showed increased H4K16Ac levels. Human lung fibroblasts with siRNA Mof silencing demonstrated reduced H4K16Ac, and significantly down-regulated profibrotic genes, such as α-smooth muscle actin (α-SMA), collagen I, Nox4, and survivin. ChIP assays confirmed the associations of these pro-fibrotic genes' promoter region with H4K16Ac, while in siRNA Mof transfected cells the promoter/H4K16Ac associations were depleted. RNA-seq data demonstrated that Mof knockdown altered gene expression and cellular pathways, including cell damage and repair. In the aging mice model of persistent lung fibrosis, 18-month old mice given intra-nasal siRNA Mof from week 3 to 6 following bleomycin injury showed improved lung architecture, decreased total hydroxyproline content and lower levels of H4K16Ac. Conclusions: These results indicate a critical epigenetic regulatory role for histone H4K16Ac in the pathogenesis of pulmonary fibrosis, which will aid in the development of novel therapeutic strategies for age-related diseases such as IPF.

PMID:34976199 | PMC:PMC8692895 | DOI:10.7150/thno.62760

Lung India. 2022 Jan-Feb;39(1):27-33. doi: 10.4103/lungindia.lungindia_393_21.

ABSTRACT

BACKGROUND: Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis (IPF) has been established by multiple clinical trials. This study aims to assess the efficacy and safety of nintedanib in real-world IPF patients in India.

METHODS: Clinical records of IPF patients (prescribed with nintedanib) visiting tertiary pulmonary care center, between June 2016 and December 2019, were analyzed retrospectively. Data were analyzed for forced vital capacity (FVC), Diffusing capacity of lung for carbon monoxide(DLCO), 6-min walk distance (6-MWD). Acute exacerbations and adverse events were also analyzed.

RESULTS: A total of 76 IPF patients were prescribed with nintedanib. Drug was prescribed at 100 and 150 mg BD dose to 37 and 39 patients. Ten patients (13.1%), of which eight were over the age of 60 years, died during the study period. Only 42 patients visited for follow-up. Mean baseline FVC was 1.67 L and mean annualized absolute change in FVC and FVC % predicted was -0.07 L and -1.80%, respectively. Mean baseline DLCO was 37.21% and mean annualized absolute change in DLCO % predicted was-2.20%. At follow-up, 1 (2.38%), 17 (40.47%), and 24 (57.14%) patients were at Deparatment of Internal Medicine stage I, II, and III, respectively. Acute exacerbations and adverse events were reported by 48 and 6 patients, respectively.

CONCLUSION: Our results support the findings from previous studies, that nintedanib leads to annual decline in parameters such as FVC and DLCO and increased 6-MWD. It was found to be well tolerated in the Indian patients with IPF.

PMID:34975049 | DOI:10.4103/lungindia.lungindia_393_21

J Pak Med Assoc. 2021 Oct;71(10):2330-2334. doi: 10.47391/JPMA.01-107.

ABSTRACT

OBJECTIVE: To compare the characteristics of connective tissue disease-associated interstitial lung disease with idiopathic pulmonary fibrosis at a tertiary care hospital.

METHODS: The retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised demographical, clinical and radiological data of patients with interstitial lung disease between October 2016 and October 2017 accessed through the outpatient data registry. Data was compared in terms of characteristics and key features of patients with connective tissue disease-associated interstitial lung disease with those of idiopathic pulmonary fibrosis. Statistical analysis was done using STATA 12.

RESULTS: Of the 184 patients, 52(29.3%) had connective tissue disease-associated interstitial lung disease and 62(35%) had idiopathic pulmonary fibrosis. The most prevalent conditions among connective tissue disease-associated interstitial lung disease patients were rheumatoid arthritis 22(42.3%) and scleroderma 13(25%). Compared to patients with idiopathic pulmonary fibrosis, those with connective tissue disease-associated interstitial lung disease were predominantly younger (p<0.001) and female (p<0.001). History of gastroesophageal reflux disease was also significantly lower in connective tissue disease-associated interstitial lung disease (p=0.05).

CONCLUSIONS: Connective tissue disease-associated interstitial lung disease patients were found to be younger and predominantly female compared to patients of idiopathic pulmonary fibrosis.

PMID:34974565 | DOI:10.47391/JPMA.01-107

Toxicol Appl Pharmacol. 2021 Dec 30:115846. doi: 10.1016/j.taap.2021.115846. Online ahead of print.

ABSTRACT

BMS-986020, BMS-986234 and BMS-986278, are three lysophosphatidic acid receptor 1 (LPA1) antagonists that were or are being investigated for treatment of idiopathic pulmonary fibrosis (IPF). Hepatobiliary toxicity (elevated serum AST, ALT, and ALP, plasma bile acids [BAs], and cholecystitis) was observed in a Phase 2 clinical trial with BMS-986020, and development was discontinued. In dogs and rats, the species used for the pivotal toxicology studies, there was no evidence of hepatobiliary toxicity in the dog while findings in the rat were limited to increased plasma BAs levels (6.1× control), ALT (2.9×) and bilirubin (3.4×) with no histopathologic correlates. Since neither rats nor dogs predicted clinical toxicity, follow-up studies in cynomolgus monkeys revealed hepatobiliary toxicity that included increased ALT (2.0× control) and GLDH (4.9×), bile duct hyperplasia, cholangitis, cholestasis, and cholecystitis at clinically relevant BMS-986020 exposures with no changes in plasma or liver BAs. This confirmed monkey as a relevant species for identifying hepatobiliary toxicity with BMS-986020. In order to assess whether the toxicity was compound-specific or related to LPA1 antagonism, two structurally distinct LPA1 antagonists (BMS-986234 and BMS-986278), were evaluated in rat and monkey. There were no clinical or anatomic pathology changes indicative of hepatobiliary toxicity. Mixed effects on plasma bile acids in both rat and monkey has made this biomarker not a useful predictor of the hepatobiliary toxicity. In conclusion, the nonclinical data indicate the hepatobiliary toxicity observed clinically and in monkeys administered BMS-986020 is compound specific and not mediated via antagonism of LPA1.

PMID:34974053 | DOI:10.1016/j.taap.2021.115846

BMJ Open. 2021 Dec 31;11(12):e050004. doi: 10.1136/bmjopen-2021-050004.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) has been defined as a distinctive type of chronic fibrotic disease, characterised by a progressive decline in lung function and a common histological pattern of interstitial pneumonia. To analyse the efficacy and safety of pirfenidone in the treatment of IPF, a systematic review and meta-analysis was performed.

DESIGN: This is a meta-analysis study.

PARTICIPANTS: Patients were diagnosed as IPF.

INTERVENTIONS: Use of pirfenidone.

PRIMARY AND SECONDARY OUTCOME: Progression-free survival (PFS), acute exacerbation and worsening of IPF and Impact on adverse events.

MEASURES: The inverse variance method for the random-effects model was used to summarise the dichotomous outcomes, risk ratios and 95% CIs.

RESULTS: A total of 9 randomised controlled trials with 1011 participants receiving pirfenidone and 912 controls receiving placebo were summarised. The pooled result suggested a statistically significant difference inall-cause mortality after pirfenidone use, with a summarised relative ratio of 0.51 (p<0.01). Longer PFS was observed in patients receiving pirfenidone compared with those who were given placebo (p<0.01). The IPF groups presented a high incidence of adverse events with a pooled relative ratio of 3.89 (p<0.01).

CONCLUSIONS: Pirfenidone can provide survival benefit for patients with IPF. Pirfenidone treatment was also associated with a longer PFS, a lower incidence of acute exacerbation and worsening of IPF.

PMID:34972762 | DOI:10.1136/bmjopen-2021-050004

PLoS One. 2021 Dec 31;16(12):e0254466. doi: 10.1371/journal.pone.0254466. eCollection 2021.

ABSTRACT

Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin's antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease (fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts. We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (-358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs. In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.

PMID:34972106 | DOI:10.1371/journal.pone.0254466

Nat Cell Biol. 2021 Dec 30. doi: 10.1038/s41556-021-00809-4. Online ahead of print.

ABSTRACT

Loss of alveolar type 2 cells (AEC2s) and the ectopic appearance of basal cells in the alveoli characterize severe lung injuries such as idiopathic pulmonary fibrosis (IPF). Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate into basal cells in response to fibrotic signalling in the lung mesenchyme, in vitro and in vivo. Single-cell analysis of normal hAEC2s and mesenchymal cells in organoid co-cultures revealed the emergence of pathologic fibroblasts and basaloid cells previously described in IPF. Transforming growth factor-β1 and anti-bone morphogenic protein signalling in the organoids promoted transdifferentiation. Trajectory and histologic analyses of both hAEC2-derived organoids and IPF epithelium indicated that hAEC2s transdifferentiate into basal cells through alveolar-basal intermediates that accumulate in proximity to pathologic CTHRC1hi/TGFB1hi fibroblasts. Our study indicates that hAEC2 loss and expansion of alveolar metaplastic basal cells in severe human lung injuries are causally connected through an hAEC2-basal cell lineage trajectory driven by aberrant mesenchyme.

PMID:34969962 | DOI:10.1038/s41556-021-00809-4

BMJ Open Respir Res. 2021 Dec;8(1):e001026. doi: 10.1136/bmjresp-2021-001026.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1-6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD.

METHODS AND ANALYSIS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort.

ETHICS AND DISSEMINATION: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication.

TRIAL REGISTRATION NUMBER: NCT04308681.

PMID:34969771 | DOI:10.1136/bmjresp-2021-001026