Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy.

Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan Trypanosoma cruzi. Clinical evidence revealed a correlation between fibrosis levels with impaired cardiac performance in CD patients. Therefore, we sought to analyze the effect of inhibitors of TGF-ß (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of T. cruzi chronic infection. Sirius Red/Fast Green dye was used to quantify both collagen expression and total protein amount, assessing cytotoxicity. The compounds were also used to treat C57/Bl6 mice chronically infected with T. cruzi, Brazil strain. We identified an anti-fibrotic effect in vitro for pirfenidone (TGF-ß inhibitor, IC50 114.3 µM), losmapimod (p38 inhibitor, IC50 17.6 µM) and SP600125 (c-Jun inhibitor, IC50 3.9 µM). This effect was independent of CF proliferation since these compounds do not affect T. cruzi-induced host cell multiplication as measured by BrdU incorporation. Assays of chronic infection of mice with T. cruzi have shown a reduction in heart collagen by pirfenidone. These results propose a novel approach to fibrosis therapy in CD, with the prospect of repurposing pirfenidone to prevent the onset of ECM accumulation in the hearts of the patients.

Injectable Tissue Adhesive Microgel Composite Containing Antifibrotic Drug for Vocal Fold Scarring.

Vocal fold (VF) scarring, a complex problem in laryngology, results from injury and inflammation of the layered architecture of the VFs. The resultant voice hoarseness, for which successful therapeutic options are currently limited, affects the patient's quality of life. A promising strategy to reverse this disorder is the use of antifibrotic drugs. The present study proposes a novel microbead-embedded injectable hydrogel that can sustain the release of the anti-fibrotic drug pirfenidone (PFD) for vocal fold scarring. Microbeads were developed using sodium alginate and gelatin, which were further embedded into a biomimetic and tissue adhesive gellan gum (GG) hydrogel. The microbead-embedded hydrogel exhibited improved injectability, viscoelasticity, tissue adhesiveness, degradability, and swelling compared to the hydrogel without beads. Additionally, the bead-embedded hydrogel could sustain the release of the PFD for a week. In vitro studies showed that the drug-loaded hydrogel could reduce the migration and proliferation of fibroblast cells in a dose-dependent manner. In summary, this study demonstrates the potential of a PFD-loaded injectable hydrogel with enhanced viscoelastic and tissue-adhesive properties for vocal fold scarring applications.

Real-world safety and effectiveness of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. METHODS: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. RESULTS: A total of 74 studies with 23,119 participants were included. After 12 months of treatment, the change from baseline in percent predicted FVC (%FVC) was - 0.75% for pirfenidone and - 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was - 2.32% for pirfenidone and - 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively. CONCLUSION: The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice.

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.

CTHRC1: An Emerging Hallmark of Pathogenic Fibroblasts in Lung Fibrosis.

Pulmonary fibrosis is a chronic, progressive, irreversible lung disease characterized by fibrotic scarring in the lung parenchyma. This condition involves the excessive accumulation of extracellular matrix (ECM) due to the aberrant activation of myofibroblasts in the alveolar environment. Transforming growth factor beta (TGF-ß) signaling is a crucial driver of fibrogenesis because it promotes excessive ECM deposition, thereby leading to scar formation and lung damage. A primary target of TGF-ß signaling in fibrosis is Collagen Triple Helix Repeat Containing 1 (CTHRC1), a secreted glycoprotein that plays a pivotal role in ECM deposition and wound repair. TGF-ß transcriptionally regulates CTHRC1 in response to tissue injury and controls the wound healing response through functional activity. CTHRC1 may also play an essential role in re-establishing and maintaining tissue homeostasis after wound closure by modulating both the TGF-ß and canonical Wnt signaling pathways. This dual function suggests that CTHRC1 regulates tissue remodeling and homeostasis. However, deregulated CTHRC1 expression in pathogenic fibroblasts has recently emerged as a hallmark of fibrosis in multiple organs and tissues. This review highlights recent studies suggesting that CTHRC1 can serve as a diagnostic and prognostic biomarker for fibrosis in idiopathic pulmonary fibrosis, systemic sclerosis, and post-COVID-19 lung fibrosis. Notably, CTHRC1 expression is responsive to antifibrotic drugs that target the TGF-ß pathway, such as pirfenidone and bexotegrast, indicating its potential as a biomarker of treatment success. These findings suggest that CTHRC1 may present new opportunities for diagnosing and treating patients with lung fibrosis.

PKM2/Hif-1α signal suppression involved in therapeutics of pulmonary fibrosis with microcystin-RR but not with pirfenidone.

To date there are only pirfenidone (PFD) and nintedanib to be given conditional recommendation in idiopathic pulmonary fibrosis (IPF) therapies with slowing disease progression, but neither has prospectively shown a reduced mortality. It is one of the urgent topics to find effective drugs for pulmonary fibrosis in medicine. Previous studies have demonstrated that microcystin-RR (MC-RR) effectively alleviates bleomycin-induced pulmonary fibrosis, but the mechanism has not been fully elucidated yet. We further conducted a comparison of therapeutic effect on the model animals of pulmonary fibrosis between MC-RR and PFD with histopathology and the expression of the molecular markers involved in differentiation, proliferation and metabolism of myofibroblasts, a major effector cell of tissue fibrosis. The levels of the enzyme molecules for maintaining the stability of interstitial structure were also evaluated. Our results showed that MC-RR and PFD effectively alleviated pulmonary fibrosis in model mice with a decreased signaling and marker molecules associated with myofibroblast differentiation and lung fibrotic lesion. In the meantime, both MC-RR and PFD treatment are beneficial to restore molecular dynamics of interstitial tissue and maintain the stability of interstitial architecture. Unexpectedly, MC-RR, rather than PFD, showed a significant effect on inhibiting PKM2-HIF-1α signaling and reducing the level of p-STAT3. Additionally, MC-RR showed a better inhibition effect on FGFR1 expression. Given that PKM2-HIF-1α and activated STAT3 molecular present a critical role in promoting the proliferation of myofibroblasts, MC-RR as a new strategy for IPF treatment has potential advantage over PFD.

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. Pirfenidone (PFD) and nintedanib (NDN) were both conditionally recommended in the clinical practice guideline published in 2015. Safety and tolerability are related to the risk of treatment discontinuation. Therefore, this study evaluated and compared the adverse events (AEs) of PFD and NDN in a large real-world population by analyzing data from the FDA Adverse Event Reporting System (FAERS) to provide a reference for their rational and safe use. Methods: The AEs of PFD and NDN were extracted from the FAERS database. The pharmacovigilance online analysis tool OpenVigil 2.1 was used to retrieve data from the FAERS database from the first quarter of 2012 to the second quarter of 2022. The reporting odds ratio (ROR) and proportional reporting ratio were used to detect the risk signals. Results: The database included 26,728 and 11,720 reports for PFD and NDN, respectively. The most frequent AEs of PFD and NDN were gastrointestinal disorders. The RORs for these drugs were 5.874 and 5.899, respectively. "Cardiac disorders" was the most statistically significant system order class for NDN with an ROR of 9.382 (95% confidence interval = 8.308-10.594). Furthermore, the numbers of designated medical events of PFD and NDN were 552 and 656, respectively. Notably, liver injury was reported more frequently for NDN (11.096%) than for PFD (6.076%). Conclusion: This study revealed differences in the reporting of AEs between PFD and NDN. The findings provide reference for physicians in clinical practice. Attention should be paid to the risks of cardiac disorders and liver injury associated with NDN.

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.

Pirfenidone improves voiding function by suppressing bladder fibrosis in underactive bladder rats.

Underactive bladder (UAB), characterized by a complex set of symptoms with few treatment options, can significantly reduce the quality of life of affected people. UAB is characterized by hyperplasia and fibrosis of the bladder wall as well as decreased bladder compliance. Pirfenidone is a powerful anti-fibrotic agent that inhibits the progression of fibrosis in people with idiopathic pulmonary fibrosis. In the current study, we evaluated the efficacy of pirfenidone in the treatment of bladder fibrosis in a UAB rat model. UAB was induced by crushing damage to nerve bundles in the major pelvic ganglion. Forty-two days after surgery, 1 mL distilled water containing pirfenidone (100, 300, or 500 mg/kg) was orally administered once every 2 days for a total of 10 times for 20 days to the rats in the pirfenidone-treated groups. Crushing damage to the nerve bundles caused voiding dysfunction, resulting in increased bladder weight and the level of fibrous related factors in the bladder, leading to UAB symptoms. Pirfenidone treatment improved urinary function, increased bladder weight and suppressed the expression of fibrosis factors. The results of this experiment suggest that pirfenidone can be used to ameliorate difficult-to-treat urological conditions such as bladder fibrosis. Therefore, pirfenidone treatment can be considered an option to improve voiding function in patient with incurable UAB.

Pirfenidone and Nintedanib in Pulmonary Fibrosis: Lights and Shadows.

Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases (ILD). Both drugs have side effects that affect patients in different ways and have different levels of severity, making treatment even more challenging for patients and clinicians. The present review aims to assess the effectiveness and potential complications of Pirfenidone and Nintedanib treatment regimens across various ILD diseases. A detailed search was performed in relevant articles published between 2018 and 2023 listed in PubMed, UpToDate, Google Scholar, and ResearchGate, supplemented with manual research. The following keywords were searched in the databases in all possible combinations: Nintedanib; Pirfenidone, interstitial lung disease, and idiopathic pulmonary fibrosis. The most widely accepted method for evaluating the progression of ILD is through the decline in forced vital capacity (FVC), as determined by respiratory function tests. Specifically, a decrease in FVC over a 6-12-month period correlates directly with increased mortality rates. Antifibrotic drugs Pirfenidone and Nintedanib have been extensively validated; however, some patients reported several side effects, predominantly gastrointestinal symptoms (such as diarrhea, dyspepsia, and vomiting), as well as photosensitivity and skin rashes, particularly associated with Pirfenidone. In cases where the side effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. However, further research is needed to optimize the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. Finally, other studies are requested to establish the treatments that can stop ILD progression.

Dual Drug-Loaded Coaxial Nanofiber Dressings for the Treatment of Diabetic Foot Ulcer.

Introduction: Diabetes mellitus is frequently associated with foot ulcers, which pose significant health risks and complications. Impaired wound healing in diabetic patients is attributed to multiple factors, including hyperglycemia, neuropathy, chronic inflammation, oxidative damage, and decreased vascularization. Rationale: To address these challenges, this project aims to develop bioactive, fast-dissolving nanofiber dressings composed of polyvinylpyrrolidone loaded with a combination of an antibiotic (moxifloxacin or fusidic acid) and anti-inflammatory drug (pirfenidone) using electrospinning technique to prevent the bacterial growth, reduce inflammation, and expedite wound healing in diabetic wounds. Results: The fabricated drug-loaded fibers exhibited diameters of 443 ± 67 nm for moxifloxacin/pirfenidone nanofibers and 488 ± 92 nm for fusidic acid/pirfenidone nanofibers. The encapsulation efficiency, drug loading and drug release studies for the moxifloxacin/pirfenidone nanofibers were found to be 70 ± 3% and 20 ± 1 µg/mg, respectively, for moxifloxacin, and 96 ± 6% and 28 ± 2 µg/mg, respectively, for pirfenidone, with a complete release of both drugs within 24 hours, whereas the fusidic acid/pirfenidone nanofibers were found to be 95 ± 6% and 28 ± 2 µg/mg, respectively, for fusidic acid and 102 ± 5% and 30 ± 2 µg/mg, respectively, for pirfenidone, with a release rate of 66% for fusidic acid and 80%, for pirfenidone after 24 hours. The efficacy of the prepared nanofiber formulations in accelerating wound healing was evaluated using an induced diabetic rat model. All tested formulations showed an earlier complete closure of the wound compared to the controls, which was also supported by the histopathological assessment. Notably, the combination of fusidic acid and pirfenidone nanofibers demonstrated wound healing acceleration on day 8, earlier than all tested groups. Conclusion: These findings highlight the potential of the drug-loaded nanofibrous system as a promising medicated wound dressing for diabetic foot applications.

Intra-articular sustained-release of pirfenidone as a disease-modifying treatment for early osteoarthritis.

Osteoarthritis (OA) is a major clinical challenge, and effective disease-modifying drugs for OA are still lacking due to the complicated pathology and scattered treatment targets. Effective early treatments are urgently needed to prevent OA progression. The excessive amount of transforming growth factor ß (TGFß) is one of the major causes of synovial fibrosis and subchondral bone sclerosis, and such pathogenic changes in early OA precede cartilage damage. Herein we report a novel strategy of intra-articular sustained-release of pirfenidone (PFD), a clinically-approved TGFß inhibitor, to achieve disease-modifying effects on early OA joints. We found that PFD effectively restored the mineralization in the presence of excessive amount of TGFß1 (as those levels found in patients' synovial fluid). A monthly injection strategy was then designed of using poly lactic-co-glycolic acid (PLGA) microparticles and hyaluronic acid (HA) solution to enable a sustained release of PFD (the "PLGA-PFD + HA" strategy). This strategy effectively regulated OA progression in destabilization of the medial meniscus (DMM)- induced OA mice model, including preventing subchondral bone loss in early OA and subchondral bone sclerosis in late OA, and reduced synovitis and pain with cartilage preservation effects. This finding suggests the promising clinical application of PFD as a novel disease-modifying OA drug.

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.

Results from randomized trial of pirfenidone in patients with chronic rejection (STOP-CLAD study).

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading long-term cause of poor outcomes after transplant and manifests by fibrotic remodeling of small airways and/or pleuroparenchymal fibroelastosis. This study evaluated the effect of pirfenidone on quantitative radiographic and pulmonary function assessment in patients with CLAD. METHODS: We performed a single-center, 6-month, randomized, placebo-controlled trial of pirfenidone in patients with CLAD. Randomization was stratified by CLAD phenotype. The primary outcome for this study was change in radiographic assessment of small airways disease, quantified as percentage of lung volume using parametric response mapping analysis of computed tomography scans (PRMfSAD); secondary outcomes included change in forced expiratory volume in 1 second (FEV1), change in forced vital capacity (FVC), and change in radiographic quantification of parenchymal disease (PRMPD). Linear mixed models were used to evaluate the treatment effect on outcome measures. RESULTS: The goal enrollment of 60 patients was not met due to the coronavirus disease of 2019 pandemic, with 23 patients included in the analysis. There was no significant difference over the study period between the pirfenidone vs placebo groups with regards to the observed change in PRMfSAD (+4.2% vs -0.4%; p = 0.22), FEV1 (-3.5% vs -3.6%; p = 0.97), FVC (-1.9% vs -4.6%; p = 0.41), or PRMPD (-0.6% vs -2.5%; p = 0.30). The study treatment tolerance and adverse events were generally similar between the pirfenidone and placebo groups. CONCLUSIONS: Pirfenidone had no apparent impact on radiographic evidence of allograft dysfunction or pulmonary function decline in a single-center randomized trial of CLAD patients that did not meet enrollment goals but had an acceptable tolerance and side-effect profile.

The mitigating effect of para-hydroxycinnamic acid in bleomycin-induced pulmonary fibrosis in mice through targeting oxidative, inflammatory and fibrotic pathways.

This study investigated the therapeutic benefits of para-hydroxycinnamic acid in mice with bleomycin-induced lung fibrosis. Forty male BALB/c mice were randomly assigned to four groups: normal, which received 0.9% normal saline; induced, which received a single dose of bleomycin (5 mg/kg) by oropharyngeal challenge; pirfenidone-treated; and para-hydroxycinnamic acid-treated, which challenged with bleomycin and received a daily oral dose of 300 and 50 mg/kg, respectively, from day 7 to day 21. Tissue pro-fibrotic and inflammatory cytokines, oxidative indicators, pulmonary histopathology, immunohistochemistry of fibrotic proteins and the assessment of gene expression by RT-qPCR were evaluated on day 22 after euthanizing animals. Pirfenidone and para-hydroxycinnamic acid managed to alleviate the fibrotic endpoints by statistically improving the weight index, histopathological score and reduced expression of fibrotic-related proteins in immune-stained lung sections, as well as fibrotic markers measured in serum samples. They also managed to alleviate tissue levels of oxidative stress and inflammatory and pro-fibrotic mediators. para-Hydroxycinnamic acid enhanced the expression of crucial genes associated with oxidative stress, inflammation and fibrosis in vivo. para-Hydroxycinnamic acid has demonstrated similar effectiveness to pirfenidone, suggesting it could be a promising treatment for fibrotic lung conditions by inhibiting the TGF-ß1/Smad3 pathway or through its anti-inflammatory and antioxidant properties.

Hermansky-Pudlak Syndrome with an Improvement in the Respiratory Symptoms after the Administration of Pirfenidone: A Case Report.

Herein, we report a case of Hermansky-Pudlak syndrome (HPS) in which respiratory symptoms improved with pirfenidone treatment. A 43-year-old Japanese woman with oculocutaneous albinism presented with a cough and dyspnea. High-resolution computed tomography revealed areas of reticular and frosted lung opacities. The diagnosis of HPS was confirmed by a prolonged bleeding time and HPS1 gene mutation. Generally, there is no effective treatment for interstitial pneumonia associated with HPS except for lung transplantation. In the present case, the cough and dyspnea improved with pirfenidone administration. Therefore, clinicians should administer pirfenidone in challenging transplantation cases and during the waiting period for transplantation.

Hyaluronic acid modified extracellular vesicles targeting hepatic stellate cells to attenuate hepatic fibrosis.

RATIONALE: Transforming growth factor-beta1 (TGF-ß1) plays a pivotal role in promoting hepatic fibrosis, pirfenidone (PFD) could inhibit TGF-ß1 signaling pathway to alleviate hepatic stellate cells (HSC) activation mediated hepatic fibrosis. The targeting delivery strategy of PFD to hepatic stellate cells is a challenge. Extracellular vesicles (EVs), cell-derived membranous particles are intraluminal nano-vesicles that play a vital role in intercellular communication, they also be considered as an ideal nano-carrier. METHODS: In this study, we developed a target strategy to deliver PFD to HSC with CD44 over-expression by EVs, hyaluronic acid (HA) modified DSPE-PEG2000 endows the active targeting ability of activated HSCs to PFD-loaded EVs. RESULTS: In both rat hepatic stellate cell line HSC-T6 and rat hepatocyte cell line BRL, HA@EVs-PFD demonstrated the capacity to down-regulate the expression of collagen-synthesis-related proteins and showed superior inhibition efficacy of HSC-T6 activation compared to free PFD. In hepatic fibrosis model, 4 weeks of HA@EVs-PFD treatment resulted in a reduction in liver collagen fibers, significant improvement in hepatic cell morphology, and amelioration of hepatic fibrosis. CONCLUSIONS: HA@EVs-PFD, as a drug delivery system that effectively targets and inhibits activated HSCs to treat hepatic fibrosis, holds promise as a potential therapeutic agent against hepatic fibrosis.

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.

Effects of Anti-Fibrotic Drugs on Transcriptome of Peripheral Blood Mononuclear Cells in Idiopathic Pulmonary Fibrosis.

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell-cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between "patients with IPF and healthy controls" and "before and after anti-fibrotic treatment" were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-ß/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy.

Bibliometric analysis of the pirfenidone and nintedanib in interstitial lung diseases.

Background: At the beginning of 21st century, reclassification of fibrosing interstitial lung diseases (ILD) scored academic concerning, and then propelled development. Decade before, pifenidone and nintedanib were approved for idiopathic pulmonary fibrosis, but no more drugs are yet available. To evaluate the development traits of pirfenidone and nintedanib in fibrosing ILD, including the influential country, institution, authors, keywords, and the major problems or the priorities of the field emerge and evolve, bibliometric analysis was used to summarize and draw scientific knowledge maps. Methods: We confined the words to "pirfenidone", "nintedanib", "pulmonary fibrosis", and "lung disease, interstitial". Publications were retrieved from the Web of Science Core Collection on February 24, 2024 with the search strategies. Citespace and VOSviewer were adopted for bibliometric analysis. Results: For the knowledge map of pirfenidone, a total of 4359 authors from 279 institutions in 58 countries/regions contributed to 538 studies. The United States and Italy are way ahead. Genentech Inc and the University of Turin are the institutions with the strongest influence. AM J RESP CRIT CARE is the maximized influential periodical. Raghu G was the most frequently co-cited scholar. keywords cluster demonstrated that vital capacity, safety, outcome, effectiveness, acute exacerbation, pathway, cell, collagen were the hotspots. The burst timeline of hotspots and references revealed academic transitions of pirfenidone-related studies. About the knowledge map of nintedanib, 3297 authors from 238 institutions in 47 countries/regions published 374 studies. Japan, the United States, and Italy are the most productive countries. Boehringer Ingelheim is the overriding productive institution. New ENGL J MED have important roles in reporting milestones of nintedanib. Richeldi L carried numerous capital publications to support the anti-fibrotic effect of nintedanib. From the network of co-occurrence keywords, idiopathic pulmonary fibrosis, efficacy, and safety were the hotspots. Nintedanib for systemic sclerosis-related ILD and progressive pulmonary fibrosis is the hotspot with sharp evolution recently. Conclusions: We summarized and showed developmental alterations of pirfenidone and nintedanib in fibrosing ILD through bibliographic index-based analysis. Our findings showed just dozen years sharp development period of pirfenidone and nintedanib in ILD, and identifies potential partners for interested researchers. The burst of hotspots demonstrated the evolvement of research priorities and major problems, and we observed the transition of keywords from experimental terms like mouse, bleomycin, cell, pathway, collagen, gene expression, to clinical terms including efficacy, safety, survival, acute exacerbation, and progressive pulmonary fibrosis. In the future, exploration about disparity models of drug administration, differences between early and later initiate anti-fibrotic therapy, both short-term and long-term efficacy of pirfenidone and nintedanib in fibrosing ILD, specifically in connective disease associate ILD would be emphatically concerned by pulmonologists.