Pirfenidone and nintedanib exert additive antifibrotic effects by the SPP1-AKT pathway in macrophages and fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality rates. It has been shown that pirfenidone (PFD) and nintedanib (Ofev) can slow down the decline in lung function of IPF patients, but their efficacy remains suboptimal. Some studies have suggested that the combination of PFD and Ofev may yield promising results. However, there is a lack of research on the combined application of these two medications in the treatment of IPF. A mouse model of bleomycin-induced (BLM) pulmonary fibrosis was established to investigate the impact of combination therapy on pulmonary fibrosis of mice. The findings demonstrated a significant reduction in lung tissue damage in mice treated with the combination therapy. Subsequent transcriptome analysis identified the differential gene secreted phosphoprotein 1 (SPP1), which was found to be associated with macrophages and fibroblasts based on multiple immunofluorescence staining results. Analysis of a phosphorylated protein microarray indicated that SPP1 plays a regulatory role in macrophages and fibroblasts via the AKT pathway. Consequently, the regulation of macrophages and fibroblasts in pulmonary fibrosis by the combination of PFD and Ofev is mediated by SPP1 through the AKT pathway, potentially offering a novel therapeutic option for IPF patients. Further investigation into the targeting of SPP1 for the treatment of pulmonary fibrosis is warranted.

The impact of antifibrotic use on long-term clinical outcomes in the pulmonary fibrosis foundation registry.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with a high mortality rate. The antifibrotic medications pirfenidone and nintedanib have been in use since 2014 for this disorder and are associated with improved rate of lung function decline. Less is known about their long-term outcomes outside of the clinical trial context. METHODS: The Pulmonary Fibrosis Foundation Patient Registry was used for this study. Patients with an IPF diagnosis made within a year of enrollment were included. The treated group was defined as patients receiving either pirfenidone or nintedanib for at least 180 days. The untreated group did not have any record of antifibrotic use. Demographic data, comorbidities, serial lung function, hospitalization, and vital status data were collected from the registry database. The primary outcomes were transplant-free survival, time to first respiratory hospitalization, and time to 10% absolute FVC decline. Time-to-event analyses were performed utilizing Cox proportional hazards models and the log-rank test. Model covariates included age, gender, smoking history, baseline lung function, comorbidities, and oxygen use. RESULTS: The registry contained 1212 patients with IPF; ultimately 288 patients met inclusion criteria for the treated group, and 101 patients were designated as untreated. Patients treated with antifibrotics were significantly younger (69.8 vs. 72.6 years, p = 0.008) and less likely to have smoked (61.1% ever smokers vs. 72.3% never smokers, p = 0.04). No significant differences were seen in race, gender, comorbidities, or baseline pulmonary function between groups. The primary outcome of transplant-free survival was not significantly different between the two groups (adjusted HR 0.799, 95% CI 0.534-1.197, p = 0.28). Time to respiratory hospitalization was significantly shorter in the treated group (adjusted HR 2.12, 95% CI 1.05-4.30, p = 0.04). No significant difference in time to pulmonary function decline was seen between groups. CONCLUSIONS: This multicenter study demonstrated 63% of newly diagnosed IPF patients had continuous antifibrotic usage. Antifibrotics were not associated with improved transplant-free survival or pulmonary function change but was associated with an increased hazard of respiratory hospitalization. Future studies should further investigate the role of antifibrotic therapy in clinically important outcomes in real-world patients with IPF and other progressive ILDs.

The current landscape of antifibrotic therapy across different organs: A systematic approach.

Fibrosis is a common pathological process that can affect virtually all the organs, but there are hardly any effective therapeutic options. This has led to an intense search for antifibrotic therapies over the last decades, with a great number of clinical assays currently underway. We have systematically reviewed all current and recently finished clinical trials involved in the development of new antifibrotic drugs, and the preclinical studies analyzing the relevance of each of these pharmacological strategies in fibrotic processes affecting tissues beyond those being clinically studied. We analyze and discuss this information with the aim of determining the most promising options and the feasibility of extending their therapeutic value as antifibrotic agents to other fibrotic conditions.

In vitro and in vivo Evaluation of Antifibrotic Properties of Verteporfin in a Composition of a Collagen Scaffold.

Extensive skin damage requires specialized therapy that stimulates regeneration processes without scarring. The possibility of using combination of a collagen gel application as a wound dressing and fibroblast attractant with verteporfin as an antifibrotic agent was examined in vivo and in vitro. In vitro effects of verteporfin on viability and myofibroblast markers expression were evaluated using fibroblasts isolated from human scar tissue. In vivo the collagen gel and verteporfin (individually and in combination) were applied into the wound to investigate scarring during skin regeneration: deviations in skin layer thickness, collagen synthesis, and extracellular matrix fibers were characterized. The results indicate that verteporfin reduces fibrotic phenotype by suppressing expression of the contractile protein Sm22α without inducing cell death. However, administration of verteporfin in combination with the collagen gel disrupts its ability to direct wound healing in a scarless manner, which may be related to incompatibility of the mechanisms by which collagen and verteporfin control regeneration.

Osteoprotegerin is an Early Marker of the Fibrotic Process and of Antifibrotic Treatment Responses in Ex Vivo Lung Fibrosis.

BACKGROUND: Lung fibrosis is a chronic lung disease with a high mortality rate with only two approved drugs (pirfenidone and nintedanib) to attenuate its progression. To date, there are no reliable biomarkers to assess fibrosis development and/or treatment effects for these two drugs. Osteoprotegerin (OPG) is used as a serum marker to diagnose liver fibrosis and we have previously shown it associates with lung fibrosis as well. METHODS: Here we used murine and human precision-cut lung slices to investigate the regulation of OPG in lung tissue to elucidate whether it tracks with (early) fibrosis development and responds to antifibrotic treatment to assess its potential use as a biomarker. RESULTS: OPG mRNA expression in murine lung slices was higher after treatment with profibrotic cytokines TGFß1 or IL13, and closely correlated with Fn and PAI1 mRNA expression. More OPG protein was released from fibrotic human lung slices than from the control human slices and from TGFß1 and IL13-stimulated murine lung slices compared to control murine slices. This OPG release was inhibited when murine slices were treated with pirfenidone or nintedanib. OPG release from human fibrotic lung slices was inhibited by pirfenidone treatment. CONCLUSION: OPG can already be detected during the early stages of fibrosis development and responds, both in early- and late-stage fibrosis, to treatment with antifibrotic drugs currently on the market for lung fibrosis. Therefore, OPG should be further investigated as a potential biomarker for lung fibrosis and a potential surrogate marker for treatment effect.

Vasoactive and Antifibrotic Properties of Cannabinoids and Applications to Vasospastic/Vaso-Occlusive Disorders: A Systematic Review.

BACKGROUND: Management of vasospastic and vaso-occlusive disorders is a complex challenge, with current treatments showing varied success. Cannabinoids have demonstrated both vasodilatory and antifibrotic properties, which present potential mechanisms for therapeutic relief. No existing review examines these effects in peripheral circulation in relation to vasospastic and vaso-occlusive disorders. This study aims to investigate vasodilatory and antifibrotic properties of cannabinoids in peripheral vasculature for application in vasospastic and vaso-occlusive disorders affecting the hand. METHODS: A systematic search was conducted by 2 independent reviewers across PubMed, Cochrane, Ovid MEDLINE, and CINAHL to identify studies in accordance with the determined inclusion/exclusion criteria. Information regarding study design, medication, dosage, and hemodynamic or antifibrotic effects were extracted. Descriptive statistics were used to summarize study findings as appropriate. RESULTS: A total of 584 articles were identified, and 32 were selected for inclusion. Studies were grouped by effect type: hemodynamic (n = 17, 53%) and antifibrotic (n = 15, 47%). Vasodilatory effects including reduced perfusion pressure, increased functional capillary density, inhibition of vessel contraction, and increased blood flow were reported in 82% of studies. Antifibrotic effects including reduced dermal thickening, reduced collagen synthesis, and reduced fibroblast migration were reported in 100% of studies. CONCLUSION: Overall, cannabinoids were found to have vasodilatory and antifibrotic effects on peripheral circulation via both endothelium-dependent and independent mechanisms. Our review suggests the applicability of cannabis-based medicines for vasospastic and vaso-occlusive disorders affecting the hand (eg, Raynaud disease, Buerger disease). Future research should aim to assess the effectiveness of cannabis-based medicines for these conditions.

Interstitial Lung Disease: A Review.

Importance: Interstitial lung disease (ILD) consists of a group of pulmonary disorders characterized by inflammation and/or fibrosis of the lung parenchyma associated with progressive dyspnea that frequently results in end-stage respiratory failure. In the US, ILD affects approximately 650 000 people and causes approximately 25 000 to 30 000 deaths per year. Observations: The most common forms of ILD are idiopathic pulmonary fibrosis (IPF), which accounts for approximately one-third of all cases of ILD, hypersensitivity pneumonitis, accounting for 15% of ILD cases, and connective tissue disease (CTD), accounting for 25% of ILD cases. ILD typically presents with dyspnea on exertion. Approximately 30% of patients with ILD report cough. Thoracic computed tomography is approximately 91% sensitive and 71% specific for diagnosing subtypes of ILDs such as IPF. Physiologic assessment provides important prognostic information. A 5% decline in forced vital capacity (FVC) over 12 months is associated with an approximately 2-fold increase in mortality compared with no change in FVC. Antifibrotic therapy with nintedanib or pirfenidone slows annual FVC decline by approximately 44% to 57% in individuals with IPF, scleroderma associated ILD, and in those with progressive pulmonary fibrosis of any cause. For connective tissue disease-associated ILD, immunomodulatory therapy, such as tocilizumab, rituximab, and mycophenolate mofetil, may slow decline or even improve FVC at 12-month follow-up. Structured exercise therapy reduces symptoms and improves 6-minute walk test distance in individuals with dyspnea. Oxygen reduces symptoms and improves quality of life in individuals with ILD who desaturate below 88% on a 6-minute walk test. Lung transplant may improve symptoms and resolve respiratory failure in patients with end-stage ILD. After lung transplant, patients with ILD have a median survival of 5.2 to 6.7 years compared with a median survival of less than 2 years in patients with advanced ILD who do not undergo lung transplant. Up to 85% of individuals with end-stage fibrotic ILD develop pulmonary hypertension. In these patients, treatment with inhaled treprostinil improves walking distance and respiratory symptoms. Conclusions and Relevance: Interstitial lung disease typically presents with dyspnea on exertion and can progress to respiratory failure. First-line therapy includes nintedanib or pirfenidone for IPF and mycophenolate mofetil for ILD due to connective tissue disease. Lung transplant should be considered for patients with advanced ILD. In patients with ILD, exercise training improves 6-minute walk test distance and quality of life.

[Progressive pulmonary Fibrosis]. / Progressive Pulmonale Fibrose PPF.

INTRODUCTION: Progressive pulmonary Fibrosis Abstract: Cough and dyspnea on excertion are common and early symptoms of interstitial lung diseases (ILD). Thoracic imaging (particularly computed tomography) detects such lung structural alterations early in the disease course. Knowledge of these diseases and their management is necessary in the daily business. The term "progressive pulmonary fibrosis" subsumes a heterogene group of interstitial lung diseases with a similar course of progressive fibrosis. The management of these diseases should be discussed interdisciplinary, similar to the management of the Idiopathic pulmonary fibrosis (IPF). Antifibrotic drugs are new therapeutic options.

Fluvoxamine alleviates bleomycin-induced lung fibrosis via regulating the cGAS-STING pathway.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with high mortality and limited effective therapy. Herein, we reported that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), used in depression and anxiety treatment, also exhibited therapeutic activities in IPF. Fluvoxamine inhibited cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), restrained the activation of their downstream targets, including PERK/ eIF2α/ c-Myc/ miR-9-5p/ TBPL1 and TBK1/ YAP/ JNK1/2/ Bnip3/ CaMKII/ cofilin signaling, thus attenuated the activation and migration of fibroblasts upon TGF-ß1 challenge. Fluvoxamine dose-dependently improved pulmonary function, decreased the expression of inflammatory factors, reduced excessive production of extracellular matrix, and thus alleviated bleomycin (BLM)-induced lung fibrosis in mice. Moreover, fluvoxamine at a dose of 10 mg/ kg showed similar efficacy as pirfenidone (PFD) at a dose of 30 mg/kg in a mice model of lung fibrosis. In summary, our results suggest that fluvoxamine is an effective anti-fibrotic agent for IPF.

Racial and ethnic disparities in antifibrotic therapy in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Racial disparities have been documented in care of many respiratory diseases but little is known about the impact of race on the treatment of interstitial lung diseases. The purpose of this study was to determine how race and ethnicity influence treatment of idiopathic pulmonary fibrosis. METHODS: Adults with idiopathic pulmonary fibrosis (>18 years) were identified using TriNetX database and paired-wised comparisons were performed for antifibrotic treatment among White, Black, Hispanic and Asian patients. Mortality of treated and untreated IPF patients was compared after propensity score matching for age, sex, nicotine dependence, oxygen dependence and predicted FVC. Additional comparisons were performed in subgroups of IPF patients older than 65 years of age and with lower lung function. RESULTS: Of 47,184 IPF patients identified, the majority were White (35,082), followed by Hispanic (6079), Black (5245) and Asian (1221). When subgroups were submitted to matched cohort pair-wise comparisons, anti-fibrotic usage was lower among Black patients compared to White (6.2% vs. 11.4%, p-value <0.0001), Hispanic (10.8% vs. 20.2%, p-value <0.0001) and Asian patients (9.6% vs. 14.7%, p-value = 0.0006). Similar treatment differences were noted in Black individuals older than 65 years and those with lower lung function. Mortality among White patients, but not Hispanic, Black, or Asian patients, was lower in patients on antifibrotic therapy versus not on therapy. CONCLUSION: This study demonstrated that Black IPF patients had lower antifibrotic use compared to White, Hispanic and Asian patients. Our findings suggest that urgent action is needed to understand the reason why racial disparities exist in the treatment of IPF.

[Research progress of anti-fibrotic drugs that inhibit epithelial-mesenchymal transition in pulmonary fibrosis].

Pulmonary fibrosis is the end-stage pathological change of lung diseases, which seriously affects the respiratory function of human body. A large number of studies at home and abroad have confirmed that epithelial-mesenchymal transition (EMT) is an important intermediate stage in the development of pulmonary fibrosis. Inhibition of multiple pathways upstream and downstream of EMT, such as the classical Smads pathway and non-Smads pathway of TGF-1 can effectively inhibit the process of EMT and alleviate pulmonary fibrosis. This article will review the main conclusions of the mechanism of action of EMT as a target to improve the pathology of pulmonary fibrosis so far, and provide a theoretical basis and research direction for further research and development of anti-pulmonary fibrosis drugs.

Kasugamycin Is a Novel Chitinase 1 Inhibitor with Strong Antifibrotic Effects on Pulmonary Fibrosis.

Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-ß (transforming growth factor-ß) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In in vivo bleomycin- and TGF-ß-stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-ß-associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in in vivo lungs and in vitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

Epidemiology, healthcare utilization, and related costs among patients with IPF: results from a German claims database analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive form of fibrosing interstitial pneumonia with poor survival. This study provides insight into the epidemiology, cost, and disease course of IPF in Germany. METHODS: A cohort of incident patients with IPF (n = 1737) was identified from German claims data (2014-2019). Incidence and prevalence rates were calculated and adjusted for age differences compared with the overall German population. All-cause and IPF-related healthcare resource utilization as well as associated costs were evaluated per observed person-year (PY) following the initial IPF diagnosis. Finally, Kaplan-Meier analyses were performed to assess time from initial diagnosis to disease deterioration (using three proxy measures: non-elective hospitalization, IPF-related hospitalization, long-term oxygen therapy [LTOT]); antifibrotic therapy initiation; and all-cause death. RESULTS: The cumulative incidence of IPF was estimated at 10.7 per 100,000 individuals in 2016, 10.9 in 2017, 10.5 in 2018, and 9.6 in 2019. The point prevalence rates per 100,000 individuals for the respective years were 21.7, 23.5, 24.1, and 24.1. On average, ≥ 14 physician visits and nearly two hospitalizations per PY were observed after the initial IPF diagnosis. Of total all-cause direct costs (€15,721/PY), 55.7% (€8754/PY) were due to hospitalizations and 29.1% (€4572/PY) were due to medication. Medication accounted for 49.4% (€1470/PY) and hospitalizations for 34.8% (€1034/PY) of total IPF-related direct costs (€2973/PY). Within 2 years of the initial IPF diagnosis (23.6 months), 25% of patients died. Within 5 years of diagnosis, 53.1% of patients had initiated LTOT; only 11.6% were treated with antifibrotic agents. The median time from the initial diagnosis to the first non-elective hospitalization was 5.5 months. CONCLUSION: The incidence and prevalence of IPF in Germany are at the higher end of the range reported in the literature. The main driver for all-cause cost was hospitalization. IPF-related costs were mainly driven by medication, with antifibrotic agents accounting for around one-third of the total medication costs even if not frequently prescribed. Most patients with IPF do not receive pharmacological treatment, highlighting the existing unmet medical need for effective and well-tolerated therapies.

Cost-effectiveness of the anti-fibrotics for the treatment of idiopathic pulmonary fibrosis in the United States.

BACKGROUND: The anti-fibrotic medications nintedanib and pirfenidone were approved in the United States for use in patients with idiopathic pulmonary fibrosis several years ago. While there is a growing body of evidence surrounding their clinical effectiveness, these medications are quite expensive and no prior cost-effectiveness analysis has been performed in the United States. METHODS: A previously published Markov model performed in the United Kingdom was replicated using United States data to project the lifetime costs and health benefits of treating idiopathic pulmonary fibrosis with: (1) symptom management; (2) pirfenidone; or (3) nintedanib. For the cost-effectiveness analysis, strategies were ranked by increasing costs and then checked for dominating treatment strategies. Then an incremental cost-effectiveness ratio was calculated for the dominant therapy. RESULTS: The anti-fibrotic medications were found to cost more than $110,000 per year compared to $12,291 annually for symptom management. While pirfenidone was slightly more expensive than nintedanib and provided the same amount of benefit, neither medication was found to be cost-effective in this U.S.-based analysis, with an average cost of $1.6 million to gain one additional quality-adjusted life year over symptom management. CONCLUSIONS: Though the anti-fibrotics remain the only effective treatment option for patients with idiopathic pulmonary fibrosis and the data surrounding their clinical effectiveness continues to grow, they are not considered cost-effective treatment strategies in the United States due to their high price.

Disease-specific eQTL screening reveals an anti-fibrotic effect of AGXT2 in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) poses an increasing clinical burden. Genome-wide association studies have revealed a limited contribution of genomic variants to the disease, requiring alternative but robust approaches to identify disease-associated variants and genes. We carried out a disease-specific expression quantitative trait loci (eQTL) screen to identify novel genetic factors that specifically act on NAFLD progression on the basis of genotype. METHODS: We recruited 125 Korean patients (83 with biopsy-proven NAFLD and 42 without NAFLD) and performed eQTL analyses using 21,272 transcripts and 3,234,941 genotyped and imputed single nucleotide polymorphisms. We then selected eQTLs that were detected only in the NAFLD group, but not in the control group (i.e., NAFLD-eQTLs). An additional cohort of 162 Korean individuals with NAFLD was used for replication. The function of the selected eQTL toward NAFLD development was validated using HepG2, primary hepatocytes and NAFLD mouse models. RESULTS: The NAFLD-specific eQTL screening yielded 242 loci. Among them, AGXT2, encoding alanine-glyoxylate aminotransferase 2, displayed decreased expression in patients with NAFLD homozygous for the non-reference allele of rs2291702, compared to no-NAFLD individuals with the same genotype (p = 4.79 × 10-6). This change was replicated in an additional 162 individuals, yielding a combined p value of 8.05 × 10-8 from a total of 245 patients with NAFLD and 42 controls. Knockdown of AGXT2 induced palmitate-overloaded hepatocyte death by increasing endoplasmic reticulum stress, and exacerbated NAFLD diet-induced liver fibrosis in mice, while overexpression of AGXT2 attenuated liver fibrosis and steatosis. CONCLUSIONS: We identified a new molecular role for AGXT2 in NAFLD. Our overall approach will serve as an efficient tool for uncovering novel genetic factors that contribute to liver steatosis and fibrosis in patients with NAFLD. LAY SUMMARY: Elucidating causal genes for non-alcoholic fatty liver disease (NAFLD) has been challenging due to limited tissue availability and the polygenic nature of the disease. Using liver and blood samples from 125 Korean individuals (83 with NAFLD and 42 without NAFLD), we devised a new analytic method to identify causal genes. Among the candidates, we found that AGXT2-rs2291702 protects against liver fibrosis in a genotype-dependent manner with the potential for therapeutic interventions. Our approach enables the discovery of causal genes that act on the basis of genotype.

Targeting cell-intrinsic metabolism for antifibrotic therapy.

In recent years, there have been major advances in our understanding of the mechanisms underlying fibrosis progression and regression, and how coordinated interactions between parenchymal and non-parenchymal cells impact on the fibrogenic process. Recent studies have highlighted that metabolic reprogramming of parenchymal cells, immune cells (immunometabolism) and hepatic stellate cells is required to support the energetic and anabolic demands of phenotypic changes and effector functions. In this review, we summarise how targeting cell-intrinsic metabolic modifications of the main fibrogenic cell actors may impact on fibrosis progression and we discuss the antifibrogenic potential of metabolically targeted interventions.

Modulation of Oxidative Phosphorylation with IM156 Attenuates Mitochondrial Metabolic Reprogramming and Inhibits Pulmonary Fibrosis.

Metabolic reprogramming of the myofibroblast plays a fundamental role in the pathogenesis of fibrosing interstitial lung diseases. Here, we characterized the in vitro and in vivo metabolic and antifibrotic effects of IM156, an oxidative phosphorylation (OXPHOS) modulator that acts by inhibiting protein complex 1. In vitro, IM156 inhibited transforming growth factor ß (TGFß)-dependent increases in mitochondrial oxygen consumption rate and expression of myofibroblast markers in human pulmonary fibroblasts without altering cell viability or adding to TGFß-induced increases in the extracellular acidification rate. IM156 significantly increased cellular AMP-activated protein kinase (AMPK) phosphorylation and was 60-fold more potent than metformin. In vivo, chronic oral administration of IM156 was highly distributed to major peripheral organs (i.e., lung, liver, kidney, heart) and had significant dose-related effects on the plasma metabolome consistent with OXPHOS modulation and AMPK activation. IM156 increased glycolysis, lipolysis, ß-oxidation, and amino acids and decreased free fatty acids, tricarboxylic acid cycle activity, and protein synthesis. In the murine bleomycin model of pulmonary fibrosis, daily oral administration of IM156, administered 7 days after lung injury, attenuated body/lung weight changes and reduced lung fibrosis and inflammatory cell infiltration. The plasma exposures of IM156 were comparable to well tolerated doses in human studies. In conclusion, the metabolic and antifibrotic effects of IM156 suggest that OXPHOS modulation can attenuate myofibroblast metabolic reprogramming and support testing IM156 as a therapy for idiopathic pulmonary fibrosis and other fibrotic diseases. SIGNIFICANCE STATEMENT: Fibrosing interstitial lung diseases have a poor prognosis, and current antifibrotic treatments have significant limitations. This study demonstrates that attenuation of fibrogenic metabolic remodeling, by modulation of oxidative phosphorylation with IM156, prevents myofibroblast phenotype/collagen deposition and is a potentially effective and translational antifibrotic strategy.

Pirfenidone vs. nintedanib in patients with idiopathic pulmonary fibrosis: a retrospective cohort study.

BACKGROUND: Two antifibrotic drugs, pirfenidone and nintedanib, are licensed for the treatment of patients with idiopathic pulmonary fibrosis (IPF). However, there is neither evidence from prospective data nor a guideline recommendation, which drug should be preferred over the other. This study aimed to compare pirfenidone and nintedanib-treated patients regarding all-cause mortality, all-cause and respiratory-related hospitalizations, and overall as well as respiratory-related health care costs borne by the Statutory Health Insurance (SHI). METHODS: A retrospective cohort study with SHI data was performed, including IPF patients treated either with pirfenidone or nintedanib. Stabilized inverse probability of treatment weighting (IPTW) based on propensity scores was applied to adjust for observed covariates. Weighted Cox models were estimated to analyze mortality and hospitalization. Weighted cost differences with bootstrapped 95% confidence intervals (CI) were applied for cost analysis. RESULTS: We compared 840 patients treated with pirfenidone and 713 patients treated with nintedanib. Both groups were similar regarding two-year all-cause mortality (HR: 0.90 95% CI: 0.76; 1.07), one-year all cause (HR: 1.09, 95% CI: 0.95; 1.25) and respiratory-related hospitalization (HR: 0.89, 95% CI: 0.72; 1.08). No significant differences were observed regarding total (€- 807, 95% CI: €- 2977; €1220) and respiratory-related (€- 1282, 95% CI: €- 3423; €534) costs. CONCLUSION: Our analyses suggest that the patient-related outcomes mortality, hospitalization, and costs do not differ between the two currently available antifibrotic drugs pirfenidone and nintedanib. Hence, the decision on treatment with pirfenidone versus treatment with nintedanib ought to be made case-by-case taking clinical characteristics, comorbidities, comedications, individual risk of side effects, and patients' preferences into account.

Renin angiotensin aldosterone system in pulmonary fibrosis: Pathogenesis to therapeutic possibilities.

Pulmonary fibrosis is a devastating lung disease with multifactorial etiology characterized by alveolar injury, fibroblast proliferation and excessive deposition of extracellular matrix proteins, which progressively results in respiratory failure and death. Accumulating evidence from experimental and clinical studies supports a central role of the renin angiotensin aldosterone system (RAAS) in the pathogenesis and progression of idiopathic pulmonary fibrosis. Angiotensin II (Ang II), a key vasoactive peptide of the RAAS mediates pro-inflammatory and pro-fibrotic effects on the lungs, adversely affecting organ function. Recent years have witnessed seminal discoveries in the field of RAAS. Identification of new enzymes, peptides and receptors has led to the development of several novel concepts. Of particular interest is the establishment of a protective axis of the RAAS comprising of Angiotensin converting enzyme 2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)], and the Mas receptor (the ACE2/Ang-(1-7)/Mas axis), and the discovery of a functional role for the Angiotensin type 2 (AT2) receptor. Herein, we will review our current understanding of the role of RAAS in lung fibrogenesis, provide evidence on the anti-fibrotic actions of the newly recognized RAAS components (the ACE2/Ang-(1-7)/Mas axis and AT2 receptor), discuss potential strategies and translational efforts to convert this new knowledge into effective therapeutics for PF.

Hepatic stellate cells role in the course of metabolic disorders development - A molecular overview.

Fibrosis is characterized by an abnormal accumulation of extracellular matrix (ECM) constituents in the liver parenchyma that lead to hepatic cirrhosis. After liver injury, the hepatic stellate cells (HSCs) undergo a response called "activation", transforming the cells into proliferative, fibrogenic and contractile myofibroblasts, representing the main collagen-producing cells in the injured tissue. Activated HSCs are considered as pro-inflammatory cells producing cytokines and several hepatomatogens; they are additionally involved in the recruitment of Kupffer cells, circulating monocytes and macrophages through the production of chemokines. Moreover, HSC have been proposed as being involved in the development of insulin resistance mainly mediated by their inflammatory properties, which undeniably links their activation to the development of diabetes and Non-alcoholic fatty liver disease. In addition, when the liver is injured, a complex interaction between hepatocytes and HSCs occurs, inducing mitochondrial dysfunction, which contributes to the accumulation of fats in hepatocytes that trigger to liver lipotoxicity. These mechanisms underlying the activation of HSC suggest their major role in the development of metabolic disorders. It turns out that several molecules including MicroRNAs and proteins have the ability to inhibit the activation and the proliferation of HSCs, which makes them interesting therapeutic targets for the subsequent management of metabolic conditions. This review focuses on the mechanisms and molecular pathways underlying the initiation and onset of metabolic disorders following HSCs activation, as well as on molecular therapeutic targets, which could limit their fibrogenic transdifferentiation and therefore improve the liver condition in the course of metabolic imbalance.