IDIOPATHIC PULMONARY FIBROSIS (IPF)

Abstract Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness.

Idiopathic Pulmonary Fibrosis What is Idiopathic Pulmonary Fibrosis? Idiopathic pulmonary fibrosis (IPF) is a condition that causes persistent and progressive scarring of the tiny air sacs (alveoli) in the lungs. The alveoli perform the vital functions of transferring oxygen to your blood stream from the air you breathe in, and transferring the waste product, carbon dioxide from your blood, to the air you breathe out. The amount of scar tissue irreversibly increases over time. The rate at which the disease progresses is highly variable, with some patients remaining stable for many years while others may deteriorate rapidly

Pepsin positivity (n, %) 2 (12) 0 (0) 0.379 Data are presented as meanSD unless stated otherwise. * Statistically significant. 4.4 Discussion The present study of investigation of gastro-esophageal and extra- esophageal reflux in idiopathic pulmonary fibrosis has shown significantly increased airway reflux symptoms in IPF population. However, there is no objective evidence of significant difference in H. Pylori infection or extra-esophageal reflux detected by exhaled breath pepsin analysis. The association of GERD and interstitial pulmonary fibrosis of obscure aetiology has been documented long before the term IPF was even described (Belcher 1949). More recently, Tobin and colleagues (Tobin et al.

Keywords: idiopathic pulmonary fibrosis, epidemiology, incidence, prevalence, mortality, risk factors Introduction Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic progressive fibrotic lung disease of unknown cause. 1,2 It occurs primarily in middle-aged to older adults and is characterized by the underlying histopathological pattern of usual interstitial pneumonia. Its pathobiology is complex and is hypothesized to be driven by the loss of alveolar epithelial cell integrity due to aging, genetic and epigenetic factors, and reactivation of developmental signaling pathways. 3 Progressive fibrosis with loss of normal lung tissue leads to restricted ventilation, impaired gas exchange, respiratory symptoms and exercise limitation, poor quality of life, and ultimately death. Unfortunately, there are no definitive therapies for IPF, with only one drug shown to potentially slow the progression of disease in clinical trials, 4 and surgical therapy with lung transplantation available to only a small minority of patients.

ABSTRACT Many patients with idiopathic pulmonary fibrosis (IPF) complain of chronic refractory cough. Chronic cough is a distressing and disabling symptom with a major impact on quality of life. During recent years, progress has been made in gaining insight into the pathogenesis of cough in IPF, which is most probably “ multifactorial ” and influenced by mechanical, biochemical and neurosensory changes, with an important role for comorbidities as well. Clinical trials of cough treatment in IPF are emerging, and cough is increasingly included as a secondary end-point in trials assessing new compounds for IPF. It is important that such studies include adequate end-points to assess cough both objectively and subjectively. This article summarises the latest insights into chronic cough in IPF. It describes the different theories regarding the pathophysiology of cough, reviews the different methods to assess cough and deals with recent and future developments in the treatment of cough in IPF.

*These authors contributed equally to this work. Correspondence to: Dr. Philip L Molyneaux. Fibrosis Research Group, Inflammation, Repair & Development Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College, London SW7 2BB, UK. Email: p.molyneaux@imperial.ac.uk. Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease of unknown cause. Current evidence suggests that it arises in genetically susceptible individuals as a consequence of an aberrant wound-healing response following repetitive alveolar injury. Overt respiratory infection and immunosuppression carry a high mortality, while polymorphisms in genes related to epithelial integrity and host defence predispose to IPF. Recent advances in sequencing technologies have allowed the use of molecular microbial technologies to characterise the respiratory microbiota in patients with IPF. Studies have suggested that changes in the overall bacterial burden are related to disease progression and highlighted significant differences between the microbiota in IPF subjects and healthy controls. Indeed differences in the microbiota between IPF patients may differentiate those with stable compared to progressive disease. As our understanding of the IPF microbiome evolves, along with refinement and advances in sampling and sequencing methodologies we may be able to use microbial signatures as a biomarker to guide prognostication and even treatment stratification in this devastating disease.

Keywords: cell therapy; stem cells; lung progenitor cells; preclinical studies; bleomycin; pulmonary fibrosis; clinical studies; idiopathic pulmonary fibrosis 1. Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and severe disease with no known cause. Damage to the alveolar epithelium is believed to be an important early pathogenic event in IPF. Epithelial cell damage and death result in gaps in epithelial basement membranes. The migration of fibroblasts and myofibroblasts into the alveolar space through these gaps leads to intra-alveolar fibrosis with an exaggerated accumulation of extracellular matrix (ECM) components. This fibrosis disturbs the normal lung architecture, leading to lung dysfunction and failure [ 1 – 3 ]. To date, pirfenidone and nintedanib are the only drugs approved for the treatment of IPF. Although these two drugs have shown efficacy in reducing the rate of decline in lung function and slowing the pace of disease progression, they are not able to halt disease progression [ 4 , 5 ]. Currently, it is not clear if pirfenidone or nintedanib can increase survival or improve symptoms such as dyspnoea and cough [ 4 , 5 ]. In addition, both compounds have shown significant side effects and neither is curative [ 4 , 5 ]. Due to the few options available for the treatment of IPF patients, there is a search for new therapeutic approaches. In this sense, over the last decade, several studies related to cell therapies have been conducted in both animal models and in patients with IPF in order to find new effective therapies for this devastating disease (Table 1 ).

Abstract: Major risk factors for idiopathic pulmonary fibrosis (IPF) include older age and a history of smoking, which predispose to several pulmonary and extra-pulmonary diseases. IPF can be associated with additional comorbidities through other mechanisms as either a cause or a consequence of these diseases. We review the literature regarding the management of common pulmonary and extra-pulmonary comorbidities, including chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, venous thromboem- bolism, sleep-disordered breathing, gastroesophageal reflux disease, coronary artery disease, depression and anxiety, and deconditioning. Recent studies have provided some guidance on the management of these diseases in IPF; however, most treatment recommendations are extrapolated from studies of non-IPF patients. Additional studies are required to more accurately determine the clinical features of these comorbidities in patients with IPF and to evaluate conventional treatments and management strategies that are beneficial in non-IPF populations.

Pennsylvania is the first state to create a registry for patients with IPF. The Temple Lung Center is one of five Pennsylvania institutions in this Pennsylvania Idiopathic Pulmonary Fibrosis Registry (PA-IPF Registry). The registry will not only help researchers learn more about IPF natural history, prevalence, and best methods of medical and surgical care but, equally important, will help patients learn more about their condition and improve their access to advanced specialty care, including transplantation and clinical trials.

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and one of the most frequently diagnosed interstitial lung diseases (ILDs). Although the novel antifibrotic agents pirfenidone and nintedanib attenuate the progressive decline in lung function characteristic of IPF [1], reduce the risk of hospitalisation or exacerbation [2, 3], and reduce the risk of death [3 – 5], IPF is a very severe disease where clinical decline is common. IPF is of particular interest to the lung physiologist because its clinical expression, which ranges from exertional dyspnoea occurring early in the disease to end-stage respiratory failure, is directly related to alterations in lung physiology. The aim of the present article is to review the multiple alterations in lung function in IPF. The diagnosis of IPF relies on high-resolution computed tomography (HRCT) scanning and pathological studies [6, 7], and is not discussed here. The role of lung function studies for prognostication and clinical decision making has been the focus of recent reviews [8 – 10]. Few data are available regarding the additional physiological derangements occurring during IPF exacerbations, so the present review focuses on stable or progressive IPF.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a 5-year survival that is worse than that of many cancers. Despite extensive research in recent years, the underlying pathophysiology is incompletely understood, and diagnostic and management decisions are made in the context of a multidisciplinary team [1]. Epidemiological studies have revealed a link between IPF and thrombotic vascular diseases including deep vein thrombosis (DVT), pulmonary embolism (PE) and acute coronary syndromes (ACS) [2 – 4]. Animal models of fibrosis have demonstrated an imbalance between thrombosis and fibrinolysis, which is also seen in the alveolar compartment in IPF patients [5, 6]. Recent studies have shown a systemic pro-thrombotic state in IPF [7], but clinical trials of anticoagulation have provided conflicting results [8, 9]. This review will discuss the role of the coagulation system in IPF, appraise the findings of the two clinical trials of anticoagulation in IPF and explore a role for new anticoagulants.

FIGURE 3. Alveolar lymphangiogenesis is a feature of idiopathic pulmonary fibrosis (IPF). a) Tissue sections reacted with anti-D2-40 (brown) and anti-CD34 (red) antibodies. Lymphatic vessels (D2-40+; black arrows) and blood vessels (CD- 34+; red arrows) are visible adjacent to the alveolar spaces (Alv) in early stages of disease. b, c) Presence of hyaluronic acid in IPF lung. Immunofluorescence staining with hyaluronan-binding protein of paraffin-embedded sections of IPF lung tissue shows hyaluronic acid (red) in a representative single confocal microscopy optical section. Fibroblastic areas (*) displaying positive staining for hyaluronic acid are presented as merged images of hyaluronic acid and 4’,6-diamidino-2- phenylindole (DAPI; blue) with (b) or without (c) an auto-fluorescence signal (green) and differential influence contrast. Cell nuclei were stained with DAPI. Scale bars550 mm.

with placebo. While there was no difference in the primary outcome measure of percent-predicted FVC, DLCO, or resting PaO 2 , post-hoc analysis revealed a trend toward reduced dis- ease progression in the etanercept-treated cohort. 38 This study (which many thought was well designed but underpowered) 39 may lead to larger trials examining the role of etanercept in IPF. 36 The recent NIH-sponsored Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis, which exam- ined the effect of sildenafil on the six-minute walking test in IPF patients with advanced disease, concluded that there was no physiologic improvement in patients receiving sildenafil. 40 However, symptoms were greatly improved, which the authors felt would be of benefit to patients suffering from IPF. When viewed in combination, these results underscore the need for the development of novel therapies that are efficacious for use in IPF. For this reason, pirfenidone, which has shown promising results in preclinical studies, has been proposed for use in this difficult-to-treat population.

Introduction Idiopathic pulmonary fibrosis is a rare lung disease of unknown origin which leads rapidly to death [ 1 ]. Epide- miological studies suggest that the incidence of IPF has been increasing steadily over the last two to three dec- ades [ 2 ]. Although the aetiology and the pathophysiology of IPF are still incompletely understood, two anti-fibrotic drugs, pirfenidone and nintedanib, have recently proven to be effective in slowing down disease progression and are now approved as treatments [ 3 , 4 ]. Clinical management of IPF remains difficult due to a lack of accurate indicators of disease progression, and an absence of simple short-term measures of therapeutic response [ 5 ]. Although the median survival is about 2–3 years, there is a wide spectrum of dis- ease courses ranging from slow evolving disease to quick deterioration [ 1 ].

INTRODUCTION It has now been over 25 years since the initial observation that emphysema co-exists in a proportion of patients with idiopathic pulmonary fibrosis (IPF)(1). Over the intervening period, the term combined pulmonary fibrosis and emphysema (CPFE)(2) has entered the interstitial lung disease (ILD) lexicon to describe a combination of two pathologies, namely emphysema and fibrosis, which combine to increase the probability of developing of pulmonary hypertension (PHT) when compared to patients with IPF alone(3-6). Yet what remains unclear in patients with CPFE is whether a symbiotic relationship exists between emphysema and fibrosis where the combination of the two disease processes, emphysema and fibrosis, exerts an impact greater than the sum of the individual parts on the likelihood of having PHT.

Abstract Idiopathic pulmonary fibrosis (IPF) is a prototype of lethal, chronic, progressive interstitial lung disease of unknown etiology. Over the past decade, macrophage has been recognized to play a significant role in IPF pathogenesis. Depending on the local microenvironments, macrophages can be polarized to either classically activated (M1) or alternatively activated (M2) phenotypes. In general, M1 macrophages are responsible for wound healing after alveolar epithelial injury, while M2 macrophages are designated to resolve wound healing processes or terminate inflammatory responses in the lung. IPF is a pathological consequence resulted from altered wound healing in response to persistent lung injury. In this review, we intend to summarize the current state of knowledge regarding the process of macrophage polarization and its mediators in the pathogenesis of pulmonary fibrosis. Our goal is to update the understanding of the mechanisms underlying the initiation and progression of IPF, and by which, we expect to provide help for developing effective therapeutic strategies in clinical settings.

Abstract Background: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial pneumonia causing a loss of respiratory surface area due to a proliferative fibrotic response involving hyperplastic, hypertrophic, and metaplastic epithelium, cystic honeycomb change, septal expansion, and variable inflammation. Wnt (wingless) signaling glycoproteins are known to be involved in lung development and tissue repair, and are up-regulated in patients with IPF. Based on previous qRT-PCR data showing increased Wnt7B in lungs of IPF patients, a systematic, quantitative examination of its tissue site distribution was undertaken.

HRCT: High-resolution computed tomography; IPF: Idiopathic pulmonary fibrosis; JRS: Japanese Respiratory Society; KL-6: Krebs von den Lungen-6; MMP: Matrix metalloproteinase; NHLBI: National Heart Lung and Blood Institute; PaO 2 : Arterial oxygen tension; PDGFR: Platelet-derived growth factor receptor; PMX: Polymyxin B-immobilized fiber column; TGF: Transforming growth factor; UIP: Usual interstitial pneumonia; VEGFR: Vascular endothelial growth factor receptor.

Idiopathic pulmonary fibrosis (IPF) is a chronic age-related lung disease with high mortality that is characterized by abnormal scarring of the lung parenchyma. There has been a recent attempt to define the age-associated changes predisposing individuals to develop IPF. Age- related perturbations that are increasingly found in epithelial cells and fibroblasts from IPF lungs compared with age-matched cells from normal lungs include defective autophagy, telomere attrition, altered proteostasis, and cell senescence. These divergent processes seem to converge in mitochondrial dysfunction and metabolic distress, which potentiate maladaptation to stress and susceptibility to age-related diseases such as IPF. Therapeutic approaches that target aging processes may be beneficial for halting the progression of disease and improving quality of life in IPF patients.

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a chronic inflammatory process and abnormal wound healing. Tumor Necrosis Factor alpha (TNFα) is considered to play a key role in fibroblast proliferation and increased collagen synthesis. It appears that there is a genetic predisposition to IPF. The genetic associations of TNF-α with IPF have been reported in different cohorts and revealing conflicting results. This study was conducted to evaluate the association of TNF- alpha-308 G/A polymorphism with IPF in Iranian patient by PCR-RFLP method.