Fibroblasts and platelets: a face-to-face dialogue at the heart of cardiac fibrosis.

Myocardial fibrosis is a feature found in most cardiac diseases and a key element contributing to heart failure and its progression. It has therefore become a subject of particular interest in cardiac research. Mechanisms leading to pathological cardiac remodeling and heart failure are diverse, including effects on cardiac fibroblasts, the main players in cardiac extracellular matrix synthesis, but also on cardiomyocytes, immune cells, endothelial cells, and more recently, platelets. Although transforming growth factor-ß (TGF-ß) is a primary regulator of fibrosis development, the cellular and molecular mechanisms that trigger its activation after cardiac injury remain poorly understood. Different types of anti-TGF-ß drugs have been tested for the treatment of cardiac fibrosis and have been associated with side effects. Therefore, a better understanding of these mechanisms is of great clinical relevance and could allow us to identify new therapeutic targets. Interestingly, it has been shown that platelets infiltrate the myocardium at an early stage after cardiac injury, producing large amounts of cytokines and growth factors. These molecules can directly or indirectly regulate cells involved in the fibrotic response, including cardiac fibroblasts and immune cells. In particular, platelets are known to be a major source of TGF-ß1. In this review, we have provided an overview of the classical cellular effectors involved in the pathogenesis of cardiac fibrosis, focusing on the emergent role of platelets, while discussing opportunities for novel therapeutic interventions.

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.

Antifibrotic Drugs against Idiopathic Pulmonary Fibrosis and Pulmonary Fibrosis Induced by COVID-19: Therapeutic Approaches and Potential Diagnostic Biomarkers.

The COVID-19 pandemic has had a significant impact on the health and economy of the global population. Even after recovery from the disease, post-COVID-19 symptoms, such as pulmonary fibrosis, continue to be a concern. This narrative review aims to address pulmonary fibrosis (PF) from various perspectives, including the fibrotic mechanisms involved in idiopathic and COVID-19-induced pulmonary fibrosis. On the other hand, we also discuss the current therapeutic drugs in use, as well as those undergoing clinical or preclinical evaluation. Additionally, this article will address various biomarkers with usefulness for PF prediction, diagnosis, treatment, prognosis, and severity assessment in order to provide better treatment strategies for patients with this disease.

Revolutionizing the Treatment of Idiopathic Pulmonary Fibrosis: From Conventional Therapies to Advanced Drug Delivery Systems.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease that has been well-reported in the medical literature. Its incidence has risen, particularly in light of the recent COVID-19 pandemic. Conventionally, IPF is treated with antifibrotic drugs-pirfenidone and nintedanib-along with other drugs for symptomatic treatments, including corticosteroids, immunosuppressants, and bronchodilators based on individual requirements. Several drugs and biologicals such as fluorofenidone, thymoquinone, amikacin, paclitaxel nifuroxazide, STAT3, and siRNA have recently been evaluated for IPF treatment that reduces collagen formation and cell proliferation in the lung. There has been a great deal of research into various treatment options for pulmonary fibrosis using advanced delivery systems such as liposomal-based nanocarriers, chitosan nanoparticles, PLGA nanoparticles, solid lipid nanocarriers, and other nanoformulations such as metal nanoparticles, nanocrystals, cubosomes, magnetic nanospheres, and polymeric micelles. Several clinical trials are also ongoing for advanced IPF treatments. This article elaborates on the pathophysiology of IPF, its risk factors, and different advanced drug delivery systems for treating IPF. Although extensive preclinical data is available for these delivery systems, the clinical performance and scale-up studies would decide their commercial translation.

An update on emerging drugs for the treatment of idiopathic pulmonary fibrosis: a look towards 2023 and beyond.

INTRODUCTION: Currently approved drug treatments for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, have been shown to slow lung function decline and improve clinical outcomes. Since significant advances in the understanding of pathogenetic mechanisms in IPF, novel potential agents are being tested to identify new targeted and better tolerated therapeutic strategies. AREAS COVERED: This review describes the evidence from IPF phase II and III clinical trials that have been completed or are ongoing in recent years. The literature search was performed using Medline and Clinicaltrials.org databases. Particular attention is paid to the new inhibitor of phosphodiesterase 4B (BI 1015550), being studied in a more advanced research phase. Some emerging critical issues of the pharmacological research are highlighted considering the recent outstanding failures of several phase III trials. EXPERT OPINION: An exponential number of randomized clinical trials are underway testing promising new molecules to increase treatment choices for patients with IPF and improve patients' quality of life. The next goals should aim at a deeper understanding of the pathogenic pathways of the disease with the challenging goal of being able not only to stabilize but also to reverse the ongoing fibrotic process in patients with IPF.

Natural compound fraxinellone ameliorates intestinal fibrosis in mice via direct intervention of HSP47-collagen interaction in the epithelium.

Intestinal fibrosis is a common complication of inflammatory bowel disease. There is still a lack of effective drugs for the prevention or treatment of intestinal fibrosis. Heat shock protein 47 (HSP47) plays a key role in the development of intestinal fibrosis. In this study we investigated the therapeutic potential and underlying mechanisms of fraxinellone, a degraded limonoid isolated from the root bark of Dictamnus dasycarpus, in the treatment of intestinal fibrosis. Intestinal fibrosis was induced in mice by dextran sodium sulfate (DSS) treatment. DDS-treated mice were administered fraxinellone (7.5, 15, 30 mg·kg-1·d-1, i.g.) for 45 days. We showed that fraxinellone administration dose-dependently alleviated DSS-induced intestinal impairments, and reduced the production of intestinal fibrosis biomarkers such as α-smooth muscle actin (SMA), collagen I, hydroxyproline, fibronectin and laminin, and cytokines such as TGF-ß, TNF-α and IL-ß. We then established in vitro intestinal fibrosis cell models in SW480 and HT-29 cells, and demonstrated that treatment with fraxinellone (3, 10, 30 µM) significantly relieved TGF-ß-induced fibrosis responses by inhibiting the TGF-ß/Smad2/3 signaling pathway. Molecular docking suggested that the fraxinellone might disrupt the interaction between HSP47 and collagen, which was confirmed by coimmunoprecipitation experiments. SPR analysis showed that fraxinellone had a high affinity for HSP47 with a Kd value of 3.542 × 10-5 M. This study provides a new example of HSP47-collagen intervention by a natural compound and has important implications for the clinical treatment of inflammation-induced issue fibrosis.

Improved Survival of IPF patients Treated With Antifibrotic Drugs Compared With Untreated Patients.

PURPOSE: Pirfenidone and nintedanib unequivocally inhibit FVC decline, but have been inconsistently linked to reduced mortality in phase III studies. On the contrary, real-world data show a survival benefit of antifibrotic drugs. However, it is unknown what this benefit is across different Gender, Age, and Physiology (GAP) stages. RESEARCH QUESTIONS: Is there a difference in transplant-free (TPF) survival of IPF patients receiving antifibrotic drugs (IPFAF) compared with an untreated cohort (IPFnon-AF)? Is this different for patients with GAP stage I, II, or III. METHODS: This is a single-center observational cohort study using prospectively included patients diagnosed with IPF between 2008-2018. Primary outcomes were TPF survival difference and 1-, 2-, and 3-year cumulative mortality for IPFAF and IPFnon-AF. This was repeated after stratification for GAP stage. RESULTS: In total, 457 patients were included. The median transplant-free survival was 3.4 years in IPFAF (n = 313) and 2.2 years in IPFnon-AF (n = 144, p = 0.005). For GAP stage II, a median survival of 3.1 and 1.7 years was noted for IPFAF (n = 143) and IPFnon-AF (n = 59, p < 0.001), respectively. A significantly lower 1-, 2-, and 3- year cumulative mortality was found for IPFAF with GAP stage II (1 yr: 7.0% vs 35.6%, 2 yr: 26.6% vs 55.9%, and 3 yr: 46.9% vs 69.5%). The 1-year cumulative mortality of IPFAF with GAP III was also significantly lower (19.0% vs 65.0%). CONCLUSION: This large real-world study showed a survival benefit in IPFAF compared with IPFnon-AF. This especially holds true for patients with GAP stage II and III.

Non-ischemic dilated cardiomyopathy and cardiac fibrosis.

Cardiac fibrosis is associated with non-ischemic dilated cardiomyopathy, increasing its morbidity and mortality. Cardiac fibroblast is the keystone of fibrogenesis, being activated by numerous cellular and humoral factors. Macrophages, CD4+ and CD8+ T cells, mast cells, and endothelial cells stimulate fibrogenesis directly by activating cardiac fibroblasts and indirectly by synthetizing various profibrotic molecules. The synthesis of type 1 and type 3 collagen, fibronectin, and α-smooth muscle actin is rendered by various mechanisms like transforming growth factor-beta/small mothers against decapentaplegic pathway, renin angiotensin system, and estrogens, which in turn alter the extracellular matrix. Investigating the underlying mechanisms will allow the development of diagnostic and prognostic tools and discover novel specific therapies. Serum biomarkers aid in the diagnosis and tracking of cardiac fibrosis progression. The diagnostic gold standard is cardiac magnetic resonance with gadolinium administration that allows quantification of cardiac fibrosis either by late gadolinium enhancement assessment or by T1 mapping. Therefore, the goal is to stop and even reverse cardiac fibrosis by developing specific therapies that directly target fibrogenesis, in addition to the drugs used to treat heart failure. Cardiac resynchronization therapy had shown to revert myocardial remodeling and to reduce cardiac fibrosis. The purpose of this review is to provide an overview of currently available data.

Self-reported Gastrointestinal Side Effects of Antifibrotic Drugs in Dutch Idiopathic Pulmonary Fibrosis patients.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is an inexorably progressive disease, which has a great impact on patients' lives. Pirfenidone and nintedanib are approved and recommended antifibrotic drugs for patients with IPF. The aim of this study was to evaluate self-reported gastrointestinal side effects of antifibrotic drugs in 176 Dutch IPF patients. METHODS: A cross-sectional web-based anonymous survey about complaints and side effects was conducted among IPF patients in the Netherlands. Logistic regression was used to quantify whether pirfenidone and nintedanib caused complaints of nausea, vomiting, diarrhoea, appetite loss, weight loss or loss of taste or smell perception. RESULTS: The questionnaire was completed by 176 IPF patients, 71 of whom used pirfenidone and 85 nintedanib, while 20 patients did not use any antifibrotic drugs. Nintedanib users reported complaints of diarrhoea, vomiting, weight loss and loss of appetite (p < 0.01). Nausea was a significant adverse reaction (p < 0.05). Pirfenidone caused increased appetite loss (p < 0.01) and the risk of weight loss (p < 0.05). The increase in loss of appetite and weight loss did not differ significantly between the two drugs. CONCLUSION: The current study showed that nintedanib causes a significant increase in diarrhoea, vomiting, weight loss and loss of appetite, while pirfenidone led to loss of appetite. Our results suggest new avenues regarding dietary recommendations for IPF patients.

Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs.

Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48h, viability was assessed by ATP and gene expression of PDGF-B and TGF-ß1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFß-pathway inhibitors, were determined. After 48h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-ß1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48h, which was further increased by PDGF-BB and TGF-ß1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFß-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-ß1 gene expression and the limited effect of the TGFß-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway.

Corneal fibrosis: From in vitro models to current and upcoming drug and gene medicines.

Fibrotic diseases are characterised by myofibroblast differentiation, uncontrolled pathological extracellular matrix accumulation, tissue contraction, scar formation and, ultimately tissue / organ dysfunction. The cornea, the transparent tissue located on the anterior chamber of the eye, is extremely susceptible to fibrotic diseases, which cause loss of corneal transparency and are often associated with blindness. Although topical corticosteroids and antimetabolites are extensively used in the management of corneal fibrosis, they are associated with glaucoma, cataract formation, corneoscleral melting and infection, imposing the need of far more effective therapies. Herein, we summarise and discuss shortfalls and recent advances in in vitro models (e.g. transforming growth factor-ß (TGF-ß) / ascorbic acid / interleukin (IL) induced) and drug (e.g. TGF-ß inhibitors, epigenetic modulators) and gene (e.g. gene editing, gene silencing) therapeutic strategies in the corneal fibrosis context. Emerging therapeutical agents (e.g. neutralising antibodies, ligand traps, receptor kinase inhibitors, antisense oligonucleotides) that have shown promise in clinical setting but have not yet assessed in corneal fibrosis context are also discussed.

Idiopathic Pulmonary Fibrosis: Where do We Stand and How Far to Go?

Idiopathic pulmonary fibrosis is a progressive and incurable lung disease characterized by collagen deposition, alveolar inflammation, fibroblast proliferation, and the destruction of lung tissue structures. It is a rare yet severe condition with a high mortality rate, typically leading to death within 3-5 years of diagnosis. The clinical presentation of idiopathic pulmonary fibrosis (IPF) involves a gradual and substantial loss of lung function, ultimately resulting in respiratory failure. Despite more than half a century of intensive research, the origin of IPF remains a mystery. Despite its unknown etiology, several genetic and non-genetic factors have been linked to IPF. Recent significant advancements have been made in the field of IPF diagnosis and treatment. Two oral small-molecule drugs, pirfenidone and nintedanib, have recently gained approval for the treatment of IPF. Pirfenidone exhibits antifibrotic, antioxidant, and anti-inflammatory properties, while nintedanib is a tyrosine kinase inhibitor with selectivity for vascular endothelial growth factor (VEGF) receptors, prostaglandin F (PGF) receptors, and fibroblast growth factor (FGF) receptors. Both of these compounds are capable of slowing down the progression of the disease with an acceptable safety profile. This review provides a brief introduction, historical background, epidemiological insights, and an exploration of various environmental risk factors that may influence the lung microenvironment and contribute to the advancement of IPF. The review also delves into the diagnosis, signaling pathways, and ongoing clinical trials worldwide. A thorough review of the literature was conducted using PubMed and Google Scholar to gather information on various aspects of IPF. Numerous potential drugs are currently under investigation in clinical trials, and the completion of this process is crucial to the ultimate goal of finding a cure for IPF patients. The investigation of the role of genes, surfactant proteins, infectious agents, biomarkers, and epigenetic changes holds the promise of offering earlier and more accurate understanding and diagnosis of IPF. This information could be instrumental in the development of new therapeutic approaches for treating IPF and is expected to be of great interest to researchers.

Efficacy and safety of pharmacological treatments for autoimmune disease-associated interstitial lung disease: A systematic review and network meta-analysis.

BACKGROUND: Immunosuppressants, biologic agents, antifibrotic drugs, and other drugs can be used to treat autoimmune disease-associated interstitial lung disease (ILD), but the preferred treatment is uncertain. We aimed to evaluate the efficacy and safety of multiple drugs in the treatment of autoimmune disease-associated ILD. METHODS: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to July 2023. Primary outcomes were percentage of predicted forced vital capacity (FVC% predicted) and discontinuations for adverse events (AEs). We estimated summary mean differences (MDs) and odds ratios (ORs) using network meta-analysis with fixed effects. RESULTS: The analysis is based on 15 RCTs involving 1832 patients. In terms of FVC% predicted, mycophenolate mofetil (MMF) (MD 1.27, 95 % credible interval [CrI] 0.08 to 2.43), cyclophosphamide (1.89, 0.10 to 3.68), rituximab (9.29, 2.79 to 15.80), tocilizumab (6.30, 3.27 to 9.34), nintedanib (1.71, 0.54 to 2.88), pirfenidone (2.03, 0.65 to 3.40) and nintedanib+MMF (2.43, 0.95 to 3.89) were more effective than placebo. Analysis based on a small sample size showed that riociguat also had good therapeutic potential when compared with placebo. By contrast, bosentan and pomalidomide showed no significant difference compared with placebo. Regarding discontinuations for AEs, nintedanib (OR 2.09, 95 %CrI 1.20 to 3.73) and pirfenidone (3.46, 1.31 to 10.56) were associated with higher dropout rates than placebo, and the combination therapy of nintedanib+MMF did not increase the risk of AEs compared with nintedanib monotherapy. CONCLUSIONS: MMF, cyclophosphamide, rituximab, tocilizumab, nintedanib and pirfenidone are effective in the treatment of autoimmune disease-associated ILD. The efficacy of riociguat and the superiority of combination therapy need to be demonstrated in more RCTs. The tolerance of nintedanib and pirfenidone is a concern, but most of their AEs are mild and controllable.

Suramin attenuates dystrophin-deficient cardiomyopathy in the mdx mouse model of duchenne muscular dystrophy.

INTRODUCTION: The purpose of this study was to determine the effects of suramin, an antifibrotic agent, on cardiac function and remodeling in mdx mice. METHODS: mdx mice (8 months old) received intraperitoneal injections of suramin twice a week for 3 months. Control mdx mice (8 months old) were injected with saline. RESULTS: Suramin improved the electrocardiography profile with the main corrections seen in S- to R-wave ratio, PR interval, and Q amplitude, and a significant decrease in the cardiomyopathy index. Suramin decreased myocardial fibrosis, inflammation, and myonecrosis. CONCLUSIONS: These findings suggest that suramin may be a new adjunctive therapy to help improve cardiomyopathy in DMD.

Liposomal Forms of Fluoroquinolones and Antifibrotics Decorated with Mannosylated Chitosan for Inhalation Drug Delivery.

The severe course of COVID-19 leads to the long-terming pulmonary diseases, such as bacterial pneumonia and post-COVID-19 pulmonary fibrosis. Thus, the essential task of biomedicine is a design of new effective drug formulations, including those for inhalation administration. In this work, we propose an approach to the creation of lipid-polymer delivery systems for fluoroquinolones and pirfenidone based on liposomes of various compositions decorated with mucoadhesive mannosylated chitosan. A generalizing study on the physicochemical patterns of the interactions of drugs with bilayers of various compositions was carried out, and the main binding sites were identified. The role of the polymer shell in the stabilization of vesicles and the delayed release of the contents has been demonstrated. For the liquid-polymer formulation of moxifloxacin, a prolonged accumulation of the drug in lung tissues was found after a single endotracheal administration to mice, significantly exceeding the control intravenous and endotracheal administration of the drug.

Progressive pulmonary fibrosis in myositis-specific antibody-positive interstitial pneumonia: a retrospective cohort study.

Objectives: Idiopathic inflammatory myopathy (IIM) frequently coexists with interstitial pneumonia (IP) and is commonly the initial or sole manifestation accompanied by positive myositis-specific autoantibodies (MSAs), even in the absence of meeting diagnostic criteria. This study aims to evaluate the proportion of progressive pulmonary fibrosis (PPF) and identify potential predictors influencing the progression of pulmonary fibrosis in patients with MSA-IP. Methods: This descriptive study employed a retrospective cohort design, enrolling patients diagnosed with interstitial pneumonia and positive MSAs at Beijing Chao-Yang Hospital in a sequential manner. Clinical data were systematically collected from the patients' medical records during regular follow-up visits conducted every 3 to 6 months. Cox regression analysis was utilized to identify independent predictors of PPF in patients with positive MSAs and interstitial pneumonia. Results: A total of 307 patients were included in the study, with 30.6% of them developing PPF during a median follow-up period of 22 months. Kaplan-Meier survival curves demonstrated a significantly lower survival in the PPF patients compared to the non-PPF patients (median 11.6 months vs. 31 months, p = 0.000). An acute/subacute onset of interstitial pneumonia (HR 3.231, 95%CI 1.936-5.392, p = 0.000), lower diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (HR 6.435, 95%CI 4.072-10.017, p = 0.001), and the presence of diffuse alveolar damage (DAD) on high-resolution computed tomography (HRCT) (HR 8.679, 95%CI 1.974-38.157, p = 0.004) emerged as independent predictors of PPF. Notably, the implementation of triple therapy comprising glucocorticoids, immunosuppressants, and antifibrotic drugs was associated with a reduced risk of developing PPF (HR 0.322, 95%CI 0.115-0.899, p = 0.031). Conclusion: Approximately 30.6% of patients with MSA-IP may develop PPF within the follow-up period. Patients presenting with an acute/subacute onset of interstitial pneumonia, lower predicted DLCO SB% and evidence of DAD on HRCT are more susceptible to developing PPF. Conversely, the administration of triple therapy appears to serve as a protective factor against the development of PPF in patients with MSA-IP.

ROS/RNS as molecular signatures of chronic liver diseases.

The liver can succumb to oxidant damage during the development of chronic liver diseases. Despite their physiological relevance to hepatic homeostasis, excessive reactive oxygen/nitrogen species (ROS/RNS) production under pathological conditions is detrimental to all liver constituents. Chronic oxidative stress coupled to unresolved inflammation sets in motion the activation of profibrogenic hepatic stellate cells (HSCs) and later pathogenesis of liver fibrosis, cirrhosis, and liver cancer. The liver antioxidant and repair systems, along with autophagic and ferroptotic machineries, are implicated in the onset and trajectory of disease development. In this review, we discuss the ROS/RNS-related mechanisms underlying liver fibrosis of distinct etiologies and highlight preclinical and clinical trials of antifibrotic therapies premised on remediating oxidative/nitrosative stress in hepatocytes or targeting HSC activation.

Benefits of Pulmonary Rehabilitation in Patients with Idiopathic Pulmonary Fibrosis Receiving Antifibrotic Drug Treatment.

Background: Although patients with idiopathic pulmonary fibrosis (IPF) often receive treatment with antifibrotic drugs (AFDs) and pulmonary rehabilitation (PR) concurrently, there are no reports on the effect of PR on patients with IPF receiving AFDs. Therefore, we investigated the effect of PR on patients with IPF receiving AFDs. Methods: Eighty-seven eligible patients with IPF (61 male; 72.0 ± 8.1 years; GAP severity stage I/II/III: 26/32/12) were recruited for the study. Patients who completed a 3-month outpatient PR program and those who did not participate were classified into four groups according to use of AFDs: PR group (n = 29), PR+AFD group (n = 11), treatment-free observational group (control group; n = 26), and AFD group (n = 21). There was no significant difference in age, sex, or severity among the groups. Patients were evaluated for physical functions such as 6-min walk distance (6MWD) and muscle strength, dyspnea, and health-related quality of life (HRQOL) at baseline and at 3 months. Results: In the PR group, dyspnea and 6MWD showed significant improvement after the 3-month PR program (p < 0.05 and p < 0.01, respectively). HRQOL was significantly worse at 3 months (p < 0.05) in the AFD group, but not in the other groups. The change in 6MWD from baseline to the 3-month time point was significantly higher in the PR+AFD group than in the AFD groups (p < 0.01). Conclusions: It was suggested that AFD treatment reduced exercise tolerance and HRQOL at 3 months; however, the concurrent use of PR may prevent or mitigate these effects.

Idiopathic pulmonary fibrosis and lung cancer: targeting the complexity of the pharmacological interconnection.

INTRODUCTION: Many data already suggested that cancer and IPF are underlined by a number of common pathogenic biologic pathways. However, fewer data regards the interconnections, in terms of synergy or increased toxicities, of drugs used in cancer and IPF. Particularly, how the specific therapy influences the concurrent condition and prognostic factors of response in patients with both lung cancer and IPF are far to be clarified. Similarly, identification of features of IPF patients with higher risk of developing pulmonary adverse events when treated with chemotherapy, immune checkpoint inhibitors, TKIs, or radiotherapy is of primary importance in clinical practice. AREAS COVERED: We will discuss the scientific rationale, based on the extensive analysis of literature data, by consulting several databases for combining anticancer and antifibrotic treatments and for the design of novel therapeutic strategies. The role of immunotherapy in cancer aroused in IPF context will be discussed with specific interested, based on the continuously increasing role of immune checkpoint inhibition against lung tumors. EXPERT OPINION: This work will help to improve knowledge, based on a multidisciplinary perspective, on IPF and cancer patients, which identify an unmet clinical need. A better management during each phase of disease progression will require the design innovative trials and the development of new drugs and molecules both in the oncologic and respiratory medicine pipeline.

Pleiotropic Long-Term Effects of Atorvastatin on Posttraumatic Joint Contracture in a Rat Model.

The antifibrotic effect of atorvastatin has already been demonstrated in several organ systems. In the present study, a rat model was used to investigate the effect of atorvastatin on posttraumatic joint contracture. Forty-eight Sprague Dawley rats were equally randomized into an atorvastatin group and a control group. After initial joint trauma, knee joints were immobilized for intervals of 2 weeks (n = 16) or 4 weeks (n = 16) or immobilized for 4 weeks with subsequent remobilization for another 4 weeks (n = 16). Starting from the day of surgery, animals received either atorvastatin or placebo daily. After euthanasia at week 2, 4 or 8, joint contracture was determined, histological examinations were performed, and gene expression was assessed. The results suggest that the joint contracture was primarily arthrogenic. Atorvastatin failed to significantly affect contracture formation and showed a reduction in myofibroblast numbers to 98 ± 58 (control: 319 ± 113, p < 0.01) and a reduction in joint capsule collagen to 60 ± 8% (control: 73 ± 9%, p < 0.05) at week 2. Gene expression of α-smooth muscle actin (α-SMA), collagen type I, transforming growth factor ß1 (TGF-ß1) and interleukin-6 (IL-6) was not significantly affected by atorvastatin. Atorvastatin decreases myofibroblast number and collagen deposition but does not result in an improvement in joint mobility.