Effect of peimisine on pulmonary interstitial fibrosis induced by bleomycin in mouse pulmonary fibrosis.

Peimisine has therapeutic effects on cough, asthma, acute lung injury and liver fibrosis. However, it has not been reported whether peimisine has an inhibitory effect on pulmonary fibrosis. In current study, a mouse pulmonary interstitial fibrosis model was established to investigate the efficacy of peimisine. Mice were categorized into six groups: Control, model, pirfenidone and three peimisine multi-dose groups. After the modelling, each group was given drugs for 21 days. Mice were euthanized and the histopathology changes of the lung were compared. The contents of cytokines in serum were determined. The mRNA expression levels of related genes in the lung tissue were detected. The contents of macrophages and neutrophils in the bronchoalveolar lavage fluid (BALF) were detected. The antifibrotic effect of peimisine was validated by using MRC-5 cells. The results demonstrated that peimisine could alleviate the destruction of alveolar structure and reduce the aggregation of inflammatory cells. Peimisine could reduce the protein expression levels of cytokines in serum. The mRNA levels of related genes were regulated. The contents of macrophages and neutrophils were decreased. Peimisine had a regulatory effect on the abnormal proliferation of MRC-5 cells. The mechanism was related to regulating extra cellular matrix (ECM) and epithelial-mesenchymal transition (EMT).

Antifibrotics in rheumatoid arthritis-associated interstitial lung disease - real-world data from a nationwide cohort.

INTRODUCTION: Interstitial lung disease (ILD) is the most common pulmonary manifestation of rheumatoid arthritis (RA) and is associated with an increased mortality. Clinical trials have shown that antifibrotics (nintedanib and pirfenidone) can slow the progression of connective tissue disease-associated ILD. This study aims to evaluate the effectiveness and tolerability of antifibrotics in a national, real-world cohort of patients with RA-ILD. MATERIAL AND METHODS: We conducted an observational multicenter study of RA-ILD patients treated with antifibrotics, who were prospectively followed in Reuma.pt. Demographic and clinical data, pulmonary function tests (PFTs) results and adverse events (AEs) were collected. A linear mixed model with random intercept was used to compare PFT results within 12 (±6) months before to 12 (±6) months after antifibrotic initiation. Drug persistence was evaluated using Kaplan-Meier curves. RESULTS: We included 40 RA-ILD patients, 27 (67.5%) initially treated with nintedanib and 13 (32.5%) with pirfenidone. Most of the patients were female (55%), and current or past smokers (52.5%). At antifibrotic initiation, mean age was 70.9 ± 7.1 years and median ILD duration 5.0 [IQR 2.3-7.5] years. A total of 20 patients were included in effectiveness analysis, with the use of antifibrotics interrupting the decline of forced vital capacity (FVC; decline 300 ± 500 mL in the year before antifibrotic initiation vs. improvement of 200 ± 400 mL in the year following antifibrotic initiation, p=0.336) and total lung capacity (TLC; decline 800 ± 300 mL in the year before antifibrotic initiation vs. improvement of 600 ± 900 mL in the year following antifibrotic initiation, p=0.147). However, diffusion capacity for carbon monoxide remained in decline (3% decline in the year before antifibrotic initiation vs. 2.9% decline in the year following antifibrotic initiation, p=0.75). AEs were reported in 16 (40%) patients and led to drug discontinuation in 12 (30%). Median duration of drug persistence was 150.3 weeks (95 %CI 11.0-289.6), with no difference between nintedanib and pirfenidone (p = 0.976). CONCLUSION: This study with real-world data corroborates the usefulness of antifibrotics in stabilizing lung function, based on FVC and TLC. However, AEs were frequently reported and were the main cause for drug discontinuation.

Antifibrotic effect of disulfiram on bleomycin-induced lung fibrosis in mice and its impact on macrophage infiltration.

The accumulation of monocyte-derived macrophages in the lung tissue during inflammation is important for the pathogenesis of fibrotic lung disease. Deficiencies in chemokine receptors CCR2 and CCR5 and their ligands, which mediate monocyte/macrophage migration, ameliorate bleomycin (BLM)-induced lung fibrosis. Disulfiram (DSF), which is used to treat alcoholism because of its aldehyde dehydrogenase (ALDH)-inhibiting effect, inhibits monocyte/macrophage migration by inhibiting FROUNT, an intracellular regulator of CCR2/CCR5 signalling. Here, we investigated the antifibrotic effect of oral DSF administration in a mouse model of BLM-induced lung fibrosis, focusing on macrophage response and fibrosis progression. The direct inhibitory activity of DSF on monocyte migration was measured using the Boyden chamber assay and compared with that of DSF-related inhibitors with different FROUNT-inhibition activities. Quantitative PCR was used to determine the expression of fibrosis-promoting genes in the lung tissue. DSF significantly suppressed macrophage infiltration into lung tissues and attenuated BLM-induced lung fibrosis. DSF and its metabolites, diethyldithiocarbamate (DDC) and copper diethyldithiocarbamate (Cu(DDC)2), inhibited monocyte migration toward the culture supernatant of primary mouse lung cells mainly comprising CCL2, whereas cyanamide, another ALDH inhibitor, did not. DSF, with higher inhibitory activity against FROUNT than DDC and Cu(DDC)2, inhibited monocyte migration most strongly. In BLM-induced fibrotic lung tissues, profibrotic factors were highly expressed but were reduced by DSF treatment. These results suggest DSF inhibits macrophage infiltration, which might be attributed to its inhibitory effect on FROUNT, and attenuates BLM-induced lung fibrosis. In addition, multiplex immunofluorescence imaging revealed reduced infiltration of S100A4+ macrophages into the lungs in DSF-treated mice and high expression of FROUNT in S100A4+ macrophages in idiopathic pulmonary fibrosis (IPF). These findings underscore the potential of macrophage-targeted therapy with DSF as a promising drug repositioning approach for treating fibrotic lung diseases, including IPF.

Precision-cut liver slices as an ex vivo model to evaluate antifibrotic therapies for liver fibrosis and cirrhosis.

BACKGROUND: Considering the lack of successful treatment options and poor prognosis for cirrhosis and cirrhosis-induced HCC, new platforms to investigate antifibrotic therapies are urgently needed. Precision-cut liver slice (PCLS) is a powerful ex vivo culture model that can supplement and potentially replace the traditional models. METHODS: PCLS were prepared from 4 different murine cirrhotic models (choline-deficient, l-amino acid-defined, high-fat diet, thioacetamide, diethylnitrosamine, and carbon tetrachloride) and compared with in vivo murine experiments, in vitro hepatic stellate cells, and human cirrhotic PCLS. RESULTS: PCLS viability in culture was stable for 72 hours. Treatment of erlotinib, an EGF receptor inhibitor, significantly inhibited profibrogenic gene expressions in PCLS from choline-deficient, l-amino acid-defined, high-fat diet or thioacetamide-induced cirrhotic rats. Erlotinib treatment of PCLS from diethylnitrosamine or carbon tetrachloride-induced cirrhotic rats inhibited the expression of profibrogenic genes, which was consistent with the impact of erlotinib on these genes in in vivo diethylnitrosamine or carbon tetrachloride-induced cirrhosis. In addition, in hepatic stellate cells at PCLS from normal mice, erlotinib treatment inhibited TGF-ß1-upregulated expression of Acta2. Similar expression results were observed in in vitro hepatic stellate cells. Expression of key regulators of fibrosis progression and regression were also significantly altered. Changes in profibrogenic gene expression under erlotinib treatment were also corroborated with human cirrhotic PCLS. CONCLUSIONS: Responses to antifibrotic interventions can be detected and quantified with PCLS at the gene expression level. The antifibrotic effects of erlotinib are consistent between PCLS models of murine cirrhosis and those observed in vivo and in vitro. These results were verified in human cirrhotic PCLS. PCLS is an excellent model for assessing antifibrotic therapies that are aligned with the principles of replacement, reduction, and refinement (3Rs), and it will benefit preclinical and clinical research for human fibrosis and cirrhosis.

Antifibrotic treatment response comparison of progressive pulmonary fibrosis and idiopathic pulmonary fibrosis.

Background/aim: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are two entities categorized as fibrotic lung diseases. With a similar clinical presentation and treatment modalities in many cases, the line differentiating these two diseases may not be evident. Hence, it was aimed herein to evaluate the effectiveness of antifibrotic treatment and the course of fibrotic lung diseases. Materials and methods: The study included patients diagnosed with IPF and PPF who were given antifibrotic treatment and followed-up for 12 months at our clinic. At the final follow-up, treatment response and radiological evaluation were investigated via high-resolution computed tomography. Results: Eighty-seven patients were included in the study (57 with IPF and 30 with PPF). Under antifibrotic treatment, there were no statistically significant decreases in the six-minute walking test, forced vital capacity, and diffusing capacity of the lungs for carbon monoxide values at 6 and 12 months posttreatment. The most common side effects were photosensitivity for patients under the pirfenidone regimen, while diarrhea was predominantly observed in the PPF group. Radiological progression was observed in 22.9% of the patients at 12 months posttreatment. Hospitalization requirements were more evident in the PPF group, with at least one hospitalization history present in 60% (n = 18) of the PPF patients compared to 12.3% (n = 7) of the IPF patients. Conclusion: A personalized approach is preferred with similar clinical profiles for both treatment modalities, with specific side effects considered.

Advances in the identification and management of progressive pulmonary fibrosis: perspective from Chinese experts.

Fibrosing interstitial lung diseases (FILDs) other than idiopathic pulmonary fibrosis (IPF) can develop into progressive pulmonary fibrosis (PPF) despite initial management. A substantial proportion of patients with non-IPF interstitial lung diseases (ILDs) progress to PPF, including connective tissue disease-associated ILD (such as rheumatoid arthritis-associated ILD, systemic sclerosis-associated ILD, and idiopathic inflammatory myositis-associated ILD), fibrosing hypersensitivity pneumonitis, and fibrosing occupational ILD. The concept of PPF emerged only recently and several studies have confirmed the impact of PPF on mortality. In addition to poor prognosis among patients with PPF, there remains a lack of consensus in the diagnosis and treatment of PPF across different types of ILDs. There is a need to raise awareness of PPF in FILDs and to explore measures to improve PPF diagnosis and treatment, which in turn could potentially reduce the progression from FILD to PPF. This review discusses the disease burden of PPF and recent advances in the management of PPF among patients with ILDs, including antifibrotic medications that have emerged as promising treatment options. Additionally, this review highlights the perspectives of expert Chinese physicians with regard to their experience in managing PPF in clinical practice.

Real-world antifibrotic treatment patterns in patients with idiopathic pulmonary fibrosis: retrospective analyses of two large healthcare administrative databases in the United States.

BACKGROUND: Real-world data on the use, healthcare resource utilization (HCRU), and associated costs of antifibrotic therapies in patients with idiopathic pulmonary fibrosis (IPF) are limited. OBJECTIVES: To assess the prevalence of antifibrotic treatment, characteristics of patients receiving treatment, discontinuation rates, and HCRU and costs associated with treatment. DESIGN: This retrospective study analyzed de-identified longitudinal and cross-sectional data, respectively, from two US claims databases: Optum's de-identified Clinformatics® Data Mart Database (CDM; commercial claims, Medicare Advantage) and the Veterans Health Administration (VHA) database. The study periods were October 1, 2013-March 31, 2019 and October 1, 2014-September 30, 2019, respectively. Eligible individuals were adults with ⩾1 diagnosis claim for IPF. METHODS: Antifibrotic prevalence, patient demographics, treatment discontinuation rates, and HCRU and costs were determined separately for each cohort and described using summary statistics. Bivariate comparisons were analyzed using Chi-square and Student's t-tests for categorical and continuous variables, respectively. RESULTS: Overall, 4223 and 4459 eligible patients were identified in the CDM and VHA databases, respectively. Prevalence of antifibrotic uptake was 9.2% and 29.1% and the rate of index treatment discontinuation was 47% and 66% during follow-up in the CDM and VHA cohorts, respectively. Antifibrotic-treated patients were significantly younger (p < 0.0001) with lower mean Charlson Comorbidity Index scores at baseline versus untreated patients in both cohorts. In the CDM cohort, the number of outpatient and pharmacy visits was significantly higher in treated versus untreated patients during follow-up (both p < 0.0001). A similar trend was observed for the VHA cohort. Total follow-up costs in both cohorts were significantly higher in treated versus untreated patients due to higher pharmacy costs (CDM; p < 0.0001) or higher outpatient and pharmacy costs (VHA; p < 0.0001). CONCLUSION: The low prevalence of antifibrotic usage in both cohorts, together with the high rate of antifibrotic discontinuation, and increased HCRU and costs in treated versus untreated patients, support the need for novel treatment options for IPF. TRIAL REGISTRATION: Not applicable.

An antifibrotic compound that ameliorates hyperglycaemia and fat accumulation in cell and HFD mouse models.

AIMS/HYPOTHESIS: Appropriate management of blood glucose levels and the prevention of complications are important in the treatment of diabetes. We have previously reported on a compound named HPH-15 that is not only antifibrotic but also AMP-activated protein kinase (AMPK)-activating. In this study, we evaluated whether HPH-15 is useful as a therapeutic medication for diabetes. METHODS: We examined the effects of HPH-15 on AMPK activation, glucose uptake, fat accumulation and lactic acid production in L6-GLUT4, HepG2 and 3T3-L1 cells, as a model of muscle, liver and fat tissue, respectively. Additionally, we investigated the glucose-lowering, fat-accumulation-suppressing, antifibrotic and AMPK-activating effect of HPH-15 in mice fed a high-fat diet (HFD). RESULTS: HPH-15 at a concentration of 10 µmol/l increased AMPK activation, glucose uptake and membrane translocation of GLUT4 in each cell model to the same extent as metformin at 2 mmol/l. The production of lactic acid (which causes lactic acidosis) in HPH-15-treated cells was equal to or less than that observed in metformin-treated cells. In HFD-fed mice, HPH-15 lowered blood glucose from 11.1±0.3 mmol/l to 8.2±0.4 mmol/l (10 mg/kg) and 7.9±0.4 mmol/l (100 mg/kg) and improved insulin resistance. The HPH-15 (10 mg/kg) group showed the same level of AMPK activation as the metformin (300 mg/kg) group in all organs. The HPH-15-treated HFD-fed mice also showed suppression of fat accumulation and fibrosis in the liver and fat tissue; these effects were more significant than those obtained with metformin. Mice treated with high doses of HPH-15 also exhibited a 44% reduction in subcutaneous fat. CONCLUSIONS/INTERPRETATION: HPH-15 activated AMPK at lower concentrations than metformin in vitro and in vivo and improved blood glucose levels and insulin resistance in vivo. In addition, HPH-15 was more effective than metformin at ameliorating fatty liver and adipocyte hypertrophy in HFD-fed mice. HPH-15 could be effective in preventing fatty liver, a common complication in diabetic individuals. Additionally, in contrast to metformin, high doses of HPH-15 reduced subcutaneous fat in HFD-fed mice. Presumably, HPH-15 has a stronger inhibitory effect on fat accumulation and fibrosis than metformin, accounting for the reduction of subcutaneous fat. Therefore, HPH-15 is potentially a glucose-lowering medication that can lower blood glucose, inhibit fat accumulation and ameliorate liver fibrosis.

Utility of the 52-Gene Risk Score to Identify Patients with Idiopathic Pulmonary Fibrosis at Greater Risk of Mortality in the Era of Antifibrotic Therapy.

PURPOSE: We investigated whether a 52-gene signature was associated with transplant-free survival and other clinically meaningful outcomes in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry, which enrolled patients who were and were not taking antifibrotic therapy. METHODS: The 52-gene risk signature was implemented to classify patients as being at "high risk" or "low risk" of disease progression and mortality. Transplant-free survival and other outcomes were compared between patients with a low-risk versus high-risk signature. RESULTS: The 52-gene signature classified 159 patients as at low risk and 86 as at high risk; in these groups, respectively, 56.6% and 51.2% used antifibrotic therapy at enrollment. Among those taking antifibrotic therapy, patients with a low-risk versus high-risk signature were at decreased risk of death, a composite of lung transplant or death, and a composite of decline in DLco % predicted > 15%, lung transplant, or death. Similar results were observed in the overall cohort. CONCLUSIONS: These data suggest that the 52-gene signature can be used in patients with IPF treated with antifibrotic therapy to distinguish patients at higher risk of disease progression and mortality.

Corynoline protects chronic pancreatitis via binding to PSMA2 and alleviating pancreatic fibrosis.

BACKGROUND: Pancreatic fibrosis is the main pathological feature of chronic pancreatitis. There is a lack of medications that effectively alleviate or reverse pancreatic fibrosis and thus cure chronic pancreatitis. METHODS: We screened drugs that could alleviate pancreatic fibrosis from 80 traditional Chinese medicine monomers and verified their efficacy and mechanisms. RESULTS: We preliminarily identified corynoline as an antifibrotic candidate by drug screening among 80 compounds. In vitro, corynoline dose-dependently reduces collagen I synthesis in pancreatic stellate cells induced by TGF-ß1 and inhibits its activation. Furthermore, we found that corynoline could alleviate the morphological disruption, such as acinar cell atrophy, collagen deposition etc., as well as reduced pancreatic weight in mice with chronic pancreatitis. We further validated the antifibrotic effect of corynoline in mRNA and protein levels. We also found that corynoline could inhibit NF-κB signaling pathway in vitro and in vivo. Next, we identified PSMA2 as the binding protein of corynoline by Lip-SMap and validated it using DARTS. Moreover, the siRNA of PSMA2 disrupts the anti-fibrotic effect of corynoline. CONCLUSION: In conclusion, corynoline is a promising agent for the treatment of pancreatic fibrosis and chronic pancreatitis.

Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF).

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive-fibrosing lung disease with a median survival of less than 5 years. Currently, two agents, pirfenidone and nintedanib are approved for this disease, and both have been shown to reduce the rate of decline in lung function in patients with IPF. However, both have significant adverse effects and neither completely arrest the decline in lung function. AREAS COVERED: Thirty experimental agents with unique mechanisms of action that are being evaluated for the treatment of IPF are discussed. These agents work through various mechanisms of action, these include inhibition of transcription nuclear factor k-B on fibroblasts, reduced expression of metalloproteinase 7, the generation of more lysophosphatidic acids, blocking the effects of transforming growth factor ß, and reducing reactive oxygen species as examples of some unique mechanisms of action of these agents. EXPERT OPINION: New drug development has the potential to expand the treatment options available in the treatment of IPF patients. It is expected that the adverse drug effect profiles will be more favorable than current agents. It is further anticipated that these new agents or combinations of agents will arrest the fibrosis, not just slow the fibrotic process.

Impact of anti-fibrotic medications on post-COVID-19 pulmonary fibrosis: A systematic review and meta-analysis.

OBJECTIVES: The impact of anti-fibrotic medications on pulmonary fibrosis caused by COVID-19 remains inconclusive and lacks systematic investigation. This study assessed the efficacy of anti-fibrotic drugs in addressing post-COVID-19 lung fibrosis. METHODS: We searched PubMed, Web of Science, Embase, and the Cochrane Library until June 15, 2024. The meta-analysis was performed using Review Manager. Heterogeneity was evaluated utilizing I2 statistic, and publication bias was assessed via funnel plots. RESULTS: The study (CRD42024552847) included 7 trials with 496 participants. No significant differences were observed in chest CT score (SMD = -0.60, 95% CI: -1.33 to 0.12, P = 0.10), length of hospital stay (MD = -1.34, 95% CI: -4.39 to 1.70, P = 0.39), and mortality (OR = 0.91, 95% CI: 0.50 to 1.64, P = 0.75) between anti-fibrosis and standard treatment groups. Notable improvements in pulmonary function were observed with anti-fibrotic drugs, as indicated by FEV1%pred (MD = 23.95, 95% CI: 12.24 to 35.67, P < 0.0001) and FEV1/FVC (MD = 18.17, 95% CI: 11.96 to 24.38, P < 0.00001). CONCLUSIONS: Anti-fibrotic medications may help reduce fibrotic lesions and improve pulmonary function in post-COVID-19 pulmonary fibrosis, but their practical use is currently based more on theory than on solid medical evidence. Currently, in clinical practice, the use of anti-fibrotic drugs in these patients primarily relies on empirical treatment. Further clinical studies are imperative to bolster its credibility for future applications.

A systematic review and meta-analysis of the clinical benefits and adverse reactions of anti-fibrotics in non-IPF progressive fibrosing ILD.

BACKGROUND: Anti-fibrotics can reduce restrictive impairment in idiopathic pulmonary fibrosis (IPF). However, its effectiveness in non-IPF progressive fibrosing interstitial lung disease (non-IPF PF-ILD) remains uncertain. OBJECTIVE: We assess the efficacy and safety of anti-fibrotics pirfenidone and nintedanib versus placebo among non-IPF PF-ILD adult patients. METHODS: Meta-analysis was performed using PubMed, SCOPUS, and Cochrane databases to identify randomized controlled trials (RCTs). At respective centers, non-IPF PF-ILD was defined as clinical and radiological findings inconsistent with IPF and greater than 5 % forced vital capacity (FVC) decline, worsening radiological fibrosis or respiratory symptoms. RESULTS: Among seven RCTs involving 1,816 non-IPF PF-ILD patients, anti-fibrotics significantly reduced decline in FVC from baseline in milliliters (MD -66.80milliliters; P < 0.01) and percent predicted (MD -1.80 %; P < 0.01) compared to placebo. However, severity of FVC decline was less than 10 % (P = 0.33) in both groups. No significant difference in the decline of 6MWD from baseline in meters (P = 0.19) while on anti-fibrotics, although those on pirfenidone had less decline in 6MWD (MD -25.12 m; P < 0.01) versus placebo. The rates of all-cause mortality (P = 0.34), all-cause hospitalization (P = 0.44), and hospitalization for respiratory etiology (P = 0.06) were comparable in both groups. Adverse events of nausea/vomiting (54.2 % vs. 20.3 %; P < 0.01), diarrhea (65.2 % vs. 27.6 %; P = 0.02), anorexia/weight loss (23.0 % vs. 7.7 %; P < 0.01), neurological disorders (20.8 % vs. 12.6 %; P < 0.01), and events requiring therapy discontinuation were higher (18.4 % vs. 9.9 %; P < 0.01) in the anti-fibrotic group. Other adverse events of skin (P = 0.18) and respiratory disorders (P = 0.20) were equal. CONCLUSION: The advent of anti-fibrotics offers alternative treatment to reduce lung function decline.

Therapeutic approaches and novel antifibrotic agents in renal fibrosis: A comprehensive review.

Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-ß (TGF-ß) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-ß receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.

Emerging role of BMPs/BMPR2 signaling pathway in treatment for pulmonary fibrosis.

Pulmonary fibrosis is a fatal and chronic lung disease that is characterized by accumulation of thickened scar in the lungs and impairment of gas exchange. The cases with unknown etiology are referred as idiopathic pulmonary fibrosis (IPF). There are currently no effective therapeutics to cure the disease; thus, the investigation of the pathogenesis of IPF is of great importance. Recent studies on bone morphogenic proteins (BMPs) and their receptors have indicated that reduction of BMP signaling in lungs may play a significant role in the development of lung fibrosis. BMPs are members of TGF-ß superfamily, and they have been shown to play an anti-fibrotic role in combating TGF-ß-mediated pathways. The impact of BMP receptors, in particular BMPR2, on pulmonary fibrosis is growing attraction to researchers. Previous studies on BMPR2 have often focused on pulmonary arterial hypertension (PAH). Given the strong clinical association between PAH and lung fibrosis, understanding BMPs/BMPR2-mediated signaling pathway is important for development of therapeutic strategies to treat IPF. In this review, we comprehensively review recent studies regarding the biological functions of BMPs and their receptors in lungs, especially focusing on their roles in the pathogenesis of pulmonary fibrosis and fibrosis resolution.

Challenges in the management of idiopathic pulmonary fibrosis from a low- and middle-income country.

Idiopathic pulmonary fibrosis (IPF) is the most common progressive form of interstitial lung disease (ILD) that leads to gradual deterioration of lung function and ultimately death. Data from low- and middle-income countries (LMIC) on IPF is scarce. In this communication, we report the challenges encountered in managing IPF from Pakistan's largest tertiary care centre. A total of 108 patients with IPF were evaluated at the Aga Khan University Hospital in Karachi, Pakistan from January 2017 to March 2020. A significant concern was that most patients with IPF presented late during their disease. A bigger challenge encountered in clinical practice was the cost and nonavailability of antifibrotic therapy in the country until mid-2020. Successfully addressing these limitations, it is anticipated that better care will be available for the patients suffering from IPF in this part of the world.

Usefulness of Transbronchial Lung Cryobiopsy When Starting Antifibrotic Treatment and Predicting Progressive Fibrosing Interstitial Lung Disease: Descriptive Research.

BACKGROUND: Although transbronchial lung cryobiopsy (TBLC) is widely used in diagnostic algorithms for various interstitial lung diseases (ILDs), its real-world utility in the therapeutic decision-making strategy for ILD patients remains unclear, in particular, when judging the time to start antifibrotic agents. METHODS: We analyzed medical records of 40 consecutive patients with idiopathic or fibrotic hypersensitivity pneumonitis who underwent TBLC. A TBLC-based usual interstitial pneumonia (UIP) score was used to assess three morphologic descriptors: patchy fibrosis, fibroblastic foci, and honeycombing. RESULTS: In our 40 patients with ILD, the most frequent radiological feature was indeterminate for UIP (45.0%). Final diagnosis included idiopathic pulmonary fibrosis (22.5%), fibrotic nonspecific interstitial pneumonia (5.0%), fibrotic hypersensitivity pneumonitis (35.0%), and unclassifiable ILD (37.5%). Linear mixed-effects analysis showed that declines in the slopes of %FVC and %DLCO in patients with TBLC-based UIP "Score ≥ 2" were significantly steeper than those of patients with "Score ≤ 1." During follow-up of patients with Score ≥ 2 (n = 24), more than half of them (n = 17) received an antifibrotic agent, with most patients (n = 13) receiving early administration of the antifibrotic agent within 6 months after the TBLC procedure. CONCLUSIONS: TBLC-based UIP Score ≥ 2 indicated the increased possibility of a progressive fibrosis course that may prove helpful in predicting progressive pulmonary fibrosis/progressive fibrosing ILD even if disease is temporarily stabilized due to anti-inflammatory agents. Patients may benefit from early introduction of antifibrotic agents by treating clinicians.

Regulation of myofibroblast dedifferentiation in pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a lethal, progressive, and irreversible condition that has become a significant focus of medical research due to its increasing incidence. This rising trend presents substantial challenges for patients, healthcare providers, and researchers. Despite the escalating burden of pulmonary fibrosis, the available therapeutic options remain limited. Currently, the United States Food and Drug Administration has approved two drugs for the treatment of pulmonary fibrosis-nintedanib and pirfenidone. However, their therapeutic effectiveness is limited, and they cannot reverse the fibrosis process. Additionally, these drugs are associated with significant side effects. Myofibroblasts play a central role in the pathophysiology of pulmonary fibrosis, significantly contributing to its progression. Consequently, strategies aimed at inhibiting myofibroblast differentiation or promoting their dedifferentiation hold promise as effective treatments. This review examines the regulation of myofibroblast dedifferentiation, exploring various signaling pathways, regulatory targets, and potential pharmaceutical interventions that could provide new directions for therapeutic development.

Pirfenidone use in fibrotic diseases: What do we know so far?

BACKGROUND: Pirfenidone has demonstrated significant anti-inflammatory and antifibrotic effects in both animal models and some clinical trials. Its potential for antifibrotic activity positions it as a promising candidate for the treatment of various fibrotic diseases. Pirfenidone exerts several pleiotropic and anti-inflammatory effects through different molecular pathways, attenuating multiple inflammatory processes, including the secretion of pro-inflammatory cytokines, apoptosis, and fibroblast activation. OBJECTIVE: To present the current evidence of pirfenidone's effects on several fibrotic diseases, with a focus on its potential as a therapeutic option for managing chronic fibrotic conditions. FINDINGS: Pirfenidone has been extensively studied for idiopathic pulmonary fibrosis, showing a favorable impact and forming part of the current treatment regimen for this disease. Additionally, pirfenidone appears to have beneficial effects on similar fibrotic diseases such as interstitial lung disease, myocardial fibrosis, glomerulopathies, aberrant skin scarring, chronic liver disease, and other fibrotic disorders. CONCLUSION: Given the increasing incidence of chronic fibrotic conditions, pirfenidone emerges as a potential therapeutic option for these patients. However, further clinical trials are necessary to confirm its therapeutic efficacy in various fibrotic diseases. This review aims to highlight the current evidence of pirfenidone's effects in multiple fibrotic conditions.

Effect of Antifibrotic Use on Mortality in Patients with Idiopathic Pulmonary Fibrosis.

Rationale: Observational studies report a significant protective effect of antifibrotics on mortality among patients with idiopathic pulmonary fibrosis (IPF). Many of these studies, however, were subject to immortal time bias because of the mishandling of delayed antifibrotic initiation. Objectives: To evaluate the antifibrotic effect on mortality among patients with IPF using appropriate statistical methods that avoid immortal time bias. Methods: Using a large administrative database, we identified 10,289 patients with IPF, of whom 2,300 used antifibrotics. Treating delayed antifibrotic initiation as a time-dependent variable, three statistical methods were used to control baseline characteristics and avoid immortal time bias. Stratified analysis was performed for patients who initiated antifibrotics early and those who initiated treatment late. For comparison, methods that mishandle immortal time bias were performed. A simulation study was conducted to demonstrate the performance of these models in a wide range of scenarios. Results: All three statistical methods yielded nonsignificant results for the antifibrotic effect on mortality, with the stratified analysis for patients with early antifibrotic initiation suggesting evidence for reduced mortality risk (for all patients, hazard ratio, 0.89; 95% confidence interval, 0.79-1.01; P = 0.08; for patients who were 65 years or older, hazard ratio, 0.85; 95% confidence interval, 0.73-0.98; P = 0.03). Methods that mishandle immortal time bias demonstrated significantly lower mortality risk for antifibrotic users. Bias of these methods was evident in the simulation study, where appropriate methods performed well with little to no bias. Conclusions: Findings in this study did not confirm an association between antifibrotics and mortality, with a stratified analysis showing support for a potential treatment effect with early treatment initiation.