Effective Treatment For Idiopathic Pulmonary Fibrosis Research Articles

Advances in cellular senescence in idiopathic pulmonary fibrosis (Review).

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and fatal interstitial lung disease of unknown cause, with a median survival of 2-3 years. Its pathogenesis is unclear and there is currently no effective treatment for IPF. Approximately two-thirds of patients with IPF are >60 years old, with a mean age of 66 years, suggesting a link between aging and IPF. However, the mechanism by which aging promotes development of PF remains unclear. Senescence of alveolar epithelial cells and lung fibroblasts (LFs) and their senescence-associated secretion phenotype (SASP) may be involved in the occurrence and development of IPF. The present review focus on senescence of LFs and epithelial and stem cells, as well as SASP, the activation of profibrotic signaling pathways and potential treatments for pathogenesis of IPF.

Prospects for Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a severe, progressive lung disease of unknown etiology with an average worldwide prevalence of 15 per 100,000. According to the etiology, IPF is classified into sporadic, syndromic, and familial cases. Sporadic cases refer to multifactorial diseases and are associated with age, viral infections, smoking and inhalation of dust, contact with chemicals and drugs, gastroesophageal reflux disease. There were revealed an association of sporadic IPF with allelic variants of the genes AKAP13, ATP11A, DPP9, DSP, IVD, IL1RN, FAM13A, MUC5B, SFTPC, SPPL2C, TERC, TERT, TOLLIP. Syndromal IPF develops in German-Pudlak syndrome. Familial cases of the disease are caused by mutations in the genes encoding surfactant (SFTPC), mucin (MUC5B), deadenylation nuclease (PARN), components of telomere functioning (RTEL1, TERC, TERT). In 2000, the American Thoracic Society recommended glucocorticoids and cytostatics for the treatment of ELISA in order to influence the inflammatory process due to the activation of fibroblasts and their accumulation in the extracellular matrix of the lungs. These recommendations are still used by many doctors, despite the publication of reliable data on the increased mortality and hospitalizations of IPF patients taking prednisolone and azathioprine. According to recent meta-analyzes, pirfenidone (an inhibitor of the synthesis of procollagen I and II growth factors) and nintenadib (a tyrosine kinase inhibitor) are the most effective treatments for IPF. Since genetic factors play an important role in the etiopathogenesis of the disease, it is promising to search for methods of targeted therapy for IPF using specific noncoding RNAs as targets, changes in the expression of which are not specific of other bronchopulmonary diseases. These RNAs include miR-9-5p, miR-27b, miR-153, miR-184, miR-326, miR-374, miR-489, miR-630, miR-1343 (decreased expression in IPF); miR-340, miR-424, miR-487b, miR-493, lncRNA AP003419.16, lncRNA AP003419.16 (increased expression in IPF).

3'5-Dimaleamylbenzoic Acid Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by parenchymal scarring, leading progressively to alveolar architecture distortion, respiratory failure, and eventually death. Currently, there is no effective treatment for IPF. Previously, 3′5-dimaleamylbenzoic acid (3′5-DMBA), a maleimide, demonstrated pro-apoptotic, anti-inflammatory, and anti-cancer properties; however, its potential therapeutic effects on IPF have not been addressed. Bleomycin (BLM) 100 U/kg was administered to CD1 mice through an osmotic minipump. After fourteen days of BLM administration, 3′5-DMBA (6 mg/kg or 10 mg/kg) and its vehicle carboxymethylcellulose (CMC) were administered intragastrically every two days until day 26. On day 28, all mice were euthanized. The 3′5-DMBA effect was assessed by histological and immunohistochemical staining, as well as by RT-qPCR. The redox status on lung tissue was evaluated by determining the glutathione content and the GSH/GSSG ratio. 3′5-DMBA treatment re-established typical lung histological features and decreased the expression of BLM-induced fibrotic markers: collagen, α-SMA, and TGF-β1. Furthermore, 3′5-DMBA significantly reduced the expression of genes involved in fibrogenesis. In addition, it decreased reduced glutathione and increased oxidized glutathione content without promoting oxidative damage to lipids, as evidenced by the decrease in the lipid peroxidation marker 4-HNE. Therefore, 3′5-DMBA may be a promising candidate for IPF treatment.

Research Progress in the Pathogenesis of Idiopathic Pulmonary Fibrosis with Lung Cancer

特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）是一种原因不明，以弥漫性肺泡炎和肺泡结构紊乱最终导致肺间质纤维化为特征的疾病。针对IPF尚无有效的治疗手段，主要以延缓疾病进展、改善患者生活质量为主。而目前IPF合并肺癌（IPF with lung cancer, IPF-LC）的发病率越来越高，致使患者死亡率明显增加、生活质量显著下降。IPF-LC多见于男性、高龄和吸烟者，是一种临床表现缺乏特异性、无明确治疗方案、中位生存期短、预后较差的致死性疾病。目前IPF-LC发病机制及治疗方案尚不明确。本文就目前IPF-LC的危险因素、发病机制、临床特征和治疗的相关研究进展作简要综述。

The Effectiveness, Safety, and Tolerability of Pirfenidone in Idiopathic Pulmonary Fibrosis: A Retrospective Study.

In this study we aimed to investigate the effectiveness and safety profile of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in a real-life setting. Clinical records of patients diagnosed with mild-to-moderate IPF and receiving pirfenidone treatment across three centers in Turkey between January and September 2017 were retrospectively collected. Pulmonary function measurements, including percentage of forced vital capacity (FVC%) and percentage of diffusion capacity (DLCO%) were analyzed in patients who received pirfenidone treatment for at least 6months. Decline in lung function, defined as an absolute decline of at least 10% in FVC from baseline, or death at 6months was also analyzed. Safety data were included for all follow-up visits. In the pooled cohort (n = 60), patients were mostly men (73.4%) and current or former smokers (61.7%). Average baseline FVC% and DLCO% were 68.4% and 48.7%, respectively. Forty-seven patients (78.3%) had a high-resolution computed tomography scan with a definite interstitial pneumonia (UIP) pattern, and 18 patients (30%) had a surgically proven UIP pattern. Forty-six (76.7%) patients with IPF remained stable and 14 (23.3%) patients had progressed according to decline in FVC of at least 10% during the therapy course. After 6months of therapy, cough decreased in 58.3% of patients. At least one side effect due to therapy was encountered in 33 (55.0%) IPF patients. Dyspepsia (36.4%), nausea (27.3%), and rash/photosensitivity (24.2%) were the most frequent side effects in our cohort. Sixteen patients (26.7%) needed dose adjustment, one patient (1.7%) discontinued therapy, and one patient (1.7%) died in the study period. This study shows that pirfenidone seems to be an effective treatment for IPF and also had tolerable and relatively acceptable side effects. Roche.

Focus on Idiopathic Pulmonary Fibrosis: Advancing Approaches to Diagnosis, Prognosis, and Treatment

As seen in this CME online activity (available at http://courses.elseviercme.com/694), idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrotic lung disease of unknown cause that is associated with substantial health-care utilization and high rates of mortality. The clinical symptoms of IPF are nonspecific and overlap with many pulmonary and cardiac diseases making differential diagnosis challenging. The American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) guidelines strongly recommend a multidisciplinary approach to the diagnosis of interstitial lung diseases; however, there are several limitations to the feasibility of this approach in clinical practice. Although early diagnosis is relevant to any chronic, progressive, and irreversible disorder, it is crucially important that effective treatments for IPF are prescribed without delay. A window of opportunity may exist during which time treatment can have optimal outcomes. Evidence on the clinical management of IPF is rapidly evolving, and key updates were made to the most recent ATS/ERS/JRS/ALAT guidelines. The widely used combination of prednisone, azathioprine, and N-acetylcysteine has now been associated with increased risk of hospitalization and death compared with placebo in patients with IPF. These treatments and others for IPF have been mostly supportive, but recently pirfenidone and nintedanib have demonstrated efficacy in reducing functional decline and disease progression in IPF. A pooled analysis of three phase 3 studies of pirfenidone found a significant 48%reduction in all-cause mortality, and a pooled analysis of a phase 2 and two phase 3 studies of nintedanib found a significant 43%reduction in on-treatment mortality. As patient exposure to these two new drugs increases, data continue to emerge on how and when to use these medications and on how to manage their side effects. Finally, several medications targeting the fibrotic pathobiology of IPF are currently in development. Given the limited treatment options for IPF, enrollment in a clinical trial may be the best chance to delay or prevent progression of IPF. This CME-certified expert video roundtable from CHEST reviews the ATS/ERS/JRS/ALAT guidelines with a specific focus on accurate and timely diagnosis of IPF and the latest data on the treatment of IPF.

Exploitation of Novel Molecular Targets to Treat Idiopathic Pulmonary Fibrosis: A Drug Discovery Perspective.

Idiopathic pulmonary fibrosis (IPF) is the most common fibrosing lung disease and is caused by excessive lung scarring. IPF-associated severe mortality can be attributed to late diagnosis due to its generic symptoms, and more importantly due to the lack of effective therapies available. Despite extensive research in the past decades, lung transplant still remains the most effective treatment for IPF. Though two drugs recently approved by FDA, Pirfenidone and Nintedanib, have shown an ability to reduce the progression of disease. However, they have shown minimal survival benefits to patients. IPF is a multifaceted disorder with poorly understood pathophysiology. We believe that there are better therapeutic targets veiled in IPF pathophysiology, exploitation of which may improve current therapeutic approaches to the disease. We have performed an extensive literature search using several bibliographic databases for peer reviewed articles discussing molecular targets/pathways involved in the pathogenesis of the disease. Furthermore, studies involving exploitation of these therapeutic targets and potential therapeutic agents were identified. Recently, new and promising targets have been revealed from GWA studies and genetic microarrays of IPF patients. In this review, we discuss the efficacy and feasibility of several novel molecular targets including Semaphorin (SEMA) 7A, connective tissue growth factor, integrin αvβ6, caveolin-1, let 7-d, calcium activated potassium channel KCa3.1, matrix metalloproteinase-19, lysocardiolipin acetyltransferase, dimethylarginine dimethylaminohydrolase, and transglutaminase 2. These targets have all shown the potential to modulate IPF pathophysiology, thereby inhibiting disease progression. Information gained from this review will be valuable to this field, enabling the design and development of novel therapeutics for IPF.

Biopsy in idiopathic pulmonary fibrosis: back to the future

ABSTRACTIntroduction: Idiopathic Pulmonary Fibrosis (IPF) is a relentlessly progressive, fibrosing interstitial pneumonia characterized by a radiologic and/or histologic pattern of usual interstitial pneumonia (UIP). The availability of two effective anti-fibrotic drugs in IPF has encouraged the identification and treatment of patients in early stages in order to maximize clinical benefit. The ability of high-resolution computed tomography (HRCT) to identify a ‘definite’ UIP pattern is suboptimal, particularly in the absence of honeycombing. Therefore, radiologic criteria for UIP are currently being redefined. Histology represents the major source of information to define a UIP pattern. Novel and less invasive approaches (particularly cryobiopsy) to sample interstitial lung diseases have demonstrated high sensitivity and specificity. In parallel, researchers are focusing on molecular mechanisms underlying IPF with the aim to identify more specific druggable targets. Lung tissue is therefore essential for diagnostic, pathogenetic and therapeutic purposes.Areas covered: We identified and critically reviewed the most relevant recent literature related to the limitations of current radiologic criteria, new lung sampling procedures, and molecular pathways in support of the need of lung tissue to better understand IPF.Expert commentary: The development of truly effective treatments for IPF requires the identification of key pathogenetic molecules and pathways. To this end, the availability of lung tissue is vital.

Pirfenidone: A Novel Agent for the Treatment of Idiopathic Pulmonary Fibrosis

To evaluate the published clinical literature on the role of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF). A systematic literature search was performed using the key words pirfenidone or Esbriet, alone and in combination, with IPF or idiopathic pulmonary fibrosis (expanded using MESH terminology). MEDLINE (1948-September 2012) was the primary database used for search purposes. In addition, all available articles and abstracts referenced by the articles identified via literature search were included. The search was limited to English-language publications. All available clinical trials of pirfenidone pertinent to its pharmacology, pharmacokinetics, efficacy, and safety were included. Pirfenidone is the first agent specifically developed for the treatment of IPF. It has been approved for use in Europe and Japan, but not in the US. Although Phase 3 trials have shown pirfenidone to improve certain clinical (6-minute walk test) and functional (change in forced vital capacity) outcomes in patients with IPF, an independent benefit on either mortality or acute exacerbation rates has yet to be demonstrated. Until more definitive supportive data are available, international guidelines have recommended against using pirfenidone to treat most patients with IPF. Although pirfenidone appears to be an effective treatment for IPF, additional clinical trials are needed to better delineate its risk-benefit profile.

Long-Acting Human Serum Albumin-Thioredoxin Fusion Protein Suppresses Bleomycin-Induced Pulmonary Fibrosis Progression

Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory cells and reactive oxygen species (ROS), such as superoxide anion radical (O2(·-)). There is currently no effective treatment of IPF. We previously developed a human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx) designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an antioxidative and anti-inflammatory protein. In this study, we examined the therapeutic effect of HSA-Trx on an IPF animal model of bleomycin (BLM)-induced pulmonary fibrosis. A pharmacokinetic study of HSA-Trx or Trx in BLM mice showed that the plasma retention and lung distribution of Trxc was markedly improved by fusion with HSA. A weekly intravenous administration of HSA-Trx, but not Trx, ameliorated BLM-induced fibrosis, as evidenced by a histopathological analysis and pulmonary hydroxyproline levels. HSA-Trx suppressed active-transforming growth factor (TGF)-β levels in the lung and inhibited the increase of inflammatory cells in bronchoalveolar lavage fluid, pulmonary inflammatory cytokines, and oxidative stress markers. An in vitro EPR experiment using phosphate-buffered saline-stimulated neutrophils confirmed the O2(·-) scavenging ability of HSA-Trx. Furthermore, post-treatment of HSA-Trx had a suppressive effect against BLM-induced fibrosis. These results suggest that HSA-Trx has potential as a novel therapeutic agent for IPF, because of its long-acting antioxidative and anti-inflammatory modulation effects.

Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary fibrotic lung disease. The diagnostic histological changes are called usual interstitial pneumonia and are characterized by histological temporal heterogeneity, whereby normal lung tissue is interspersed with interstitial fibrosis, honeycomb cysts and fibroblast foci. Pulmonary functions show restricted volumes and capacities, preserved flows and evidence of decreased gas exchange. High-resolution computed axial tomography demonstrates evidence of fibrosis and lung remodelling such as honeycomb cysts and traction bronchiectasis. There is no known effective treatment for IPF, but lung transplantation improves survival.