Interstitial pulmonary fibrosis in an automobile body shop worker

Interstitial pulmonary fibrosis (IPF) is often of uncertain etiology and is therefore named 'idiopathic' pulmonary fibrosis. Some occupational exposures, however, are known to cause interstitial fibrosis, asbestos and silica being well-known examples. We present clinical and pathological findings of a case with IPF and the results of microchemical analysis of inorganic particulate matter in the lung tissue. A very high lung burden of inorganic contaminants was found, including silica and metallic compounds. Emphasis is given to the importance of obtaining detailed occupational histories and conducting microchemical analysis of lung tissue in order to clarify etiological factors in cases with 'idiopathic' pulmonary fibrosis.     

Integration of inflammation,fibrosis, and cancer induced by carbon nanotubes

Abstract

Carbon nanotubes (CNTs) are nanomaterials with unique physicochemical properties that are targets of great interest for industrial and commercial applications. Notwithstanding, some characteristics of CNTs are associated with adverse outcomes from exposure to pathogenic particulates, raising concerns over health risks in exposed workers and consumers. Indeed, certain forms of CNTs induce a range of harmful effects in laboratory animals, among which inflammation, fibrosis, and cancer are consistently observed for some CNTs. Inflammation, fibrosis, and malignancy are complex pathological processes that, in summation, underlie a major portion of human disease. Moreover, the functional interrelationship among them in disease pathogenesis has been increasingly recognized. The CNT-induced adverse effects resemble certain human disease conditions, such as pneumoconiosis, idiopathic pulmonary fibrosis (IPF), and mesothelioma, to some extent. Progress has been made in understanding CNT-induced pathologic conditions in recent years, demonstrating a close interconnection among inflammation, fibrosis, and cancer. Mechanistically, a number of mediators, signaling pathways, and cellular processes are identified as major mechanisms that underlie the interplay among inflammation, fibrosis, and malignancy, and serve as pathogenic bases for these disease conditions in CNT-exposed animals. These studies indicate that CNT-induced pathological effects, in particular, inflammation, fibrosis, and cancer, are mechanistically, and in some cases, causatively, interrelated. These findings generate new insights into CNT adverse effects and pathogenesis and provide new targets for exposure monitoring and drug development against inflammation, fibrosis, and cancer caused by inhaled nanomaterials.     

ILO尘肺胸片分类标准在间质性肺疾病中的应用

目的：采用ILO尘肺胸片分类方法分析胸内结节病（Sarc)及特发性肺间质纤维化（IPF）的肺内病变情况。方法：78例Sarc(Ⅱ、Ⅲ期）及25例IPF的普通X线胸片,对照ILO尘肺标准胸片分析Sarc及IPF肺内间质病变的类型和程度。结果：两种疾病肺内病变均以线状景为主,次为混合景。上、中、下肺野病变依次加重,彼此间有明显差异。IPF上、中肺野病变重于Sarc相应肺野。SarcⅢ期两个肺野变密集度也高于Ⅱ期。同种疾病左、右两则病变的类型和程度相似。结论：ILO尘肺胸片分类方法有助于间质性肺疾病肺内病的定性和定量分析。     

氧化应激在特发性肺纤维化中的作用及其机制研究进展

特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是以弥漫性肺泡炎和成纤维细胞病理性增生最终导致肺间质纤维化为病理特征的慢性进展性疾病。IPF发病机制尚未完全明确。成肌纤维细胞(myofibroblast)增多是目前学术界认为最为重要的IPF发生致病的主要机制。同时氧化/抗氧化失衡引起的氧化应激反应是其发病重要机制之一。纠正体内氧化/抗氧化失衡能减轻肺纤维化的程度,因此有望成为治疗特发性肺纤维化的一种新方法。该文就近年来氧化应激反应在IPF中的作用及其机制研究进展作一综述。     

肺癌术后肺纤维化急性加重的诊疗进展

特发性肺纤维化（IPF）是一种特殊类型的间质性肺炎,以缓慢进展为特点,其病变局限在肺部,老年人多见,一部分病例会出现急性加重的过程,表现为原有肺部病变突然恶化和致死性的呼吸衰竭,并出现新的肺部阴影和弥漫性肺泡病理改变。特发性肺纤维化急性加重（AEIPF）可发生于接受肺切除术后的原发性肺癌患者,起病通常呈急性或亚急性过程,病因尚不明确,通常认为与不明原因的肺损伤相关,起病隐匿,病情进展迅速,病死率高,而且在临床缺乏常规的预防和治疗措施,成为困扰临床医生的难题。本文就肺癌术后特发性肺纤维化急性加重的病因、发生的危险因素、预测指标、预防、治疗、预后等方面做一系统综述。     

特发性肺纤维化的组学研究进展

特发性肺纤维化(IPF)是一种原因不明的以呼吸困难和肺功能进行性恶化为特征的慢性肺纤维化性疾病,预后不良。IPF的病因尚未完全阐明,与老化、遗传、环境暴露、氧化应激和微生物-宿主防御反应有关。基因突变、转录和翻译异常、表观基因调控改变及代谢紊乱均可能影响疾病的发生和发展。近年来,采用高通量技术的组学研究从多维度揭示了IPF的发病机制,为寻找生物标志物和治疗靶点提供了新视角。本文综述了应用基因组学、转录组学、表观基因组学、蛋白质组学和代谢组学技术阐明IPF发病机制、寻找生物标志物、提供治疗靶点的最新研究进展。     

Use of transgenic mouse models to understand the origins of familial pulmonary fibrosis

Pulmonary fibrosis is an unremitting degenerative lung disease that has an associated high mortality. The major pathological features include the growth of fibroblasts, emergence of myofibroblasts and their production of extracellular matrix that distorts the peripheral lung tissue and impairs respiratory function. Efforts to pharmacologically reduce inflammation, inhibit fibroblast growth, or matrix synthesis have not been successful in ameliorating disease. Genetic mutations associated with rare hereditary forms of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF) link definitive causes to this enigmatic group of diseases. The generation of mouse models with similar genetic lesions or deficiencies is providing insight into the mechanisms that lead to fibrosis. Mutations that alter components of pulmonary surfactant or surfactant homeostasis have been associated with specific forms of ILD and/or IPF. This small but growing collection of IPF related surfactant dysfunction mutations implicate respiratory epithelial cell injury as an early event in the molecular pathogenesis and progression of fibrosis. Determining the mechanisms for genetically defined examples of IPF should be informative for investigating the larger segment of IPF where the underlying cause remains obscure.     

The footprint of TGF-β in airway remodeling of the mustard lung

Abstract

Mustard lung is a major pulmonary complication in individuals exposed to sulfur mustard (SM) gas during the Iran–Iraq war. It shares common pathological and clinical features with some chronic inflammatory lung disorders, particularly chronic obstructive pulmonary disease (COPD). Airway remodeling, which is one of the main causes of lung dysfunction and the dominant phenomenon of chronic pulmonary diseases, is seen in the mustard lung. Among all mediators involved in the remodeling process, the transforming growth factor (TGF)-β plays a pivotal role in lung fibrosis and consequently in the airway remodeling. Regarding the high levels of this mediator detected in mustard lung patients, in the present study, we have discussed the possible roles of TGF-β in airway remodeling (including epithelial layer damage, subepithelial fibrosis and angiogenesis). Finally, based on TGF-β targeting, we have reviewed new airway remodeling therapeutic approaches.     

S-allyl-l-cysteine attenuates bleomycin-induced pulmonary fibrosis and inflammation via AKT/NF-κB signaling pathway in mice

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by inflammation, multifocal fibrotic lesions and excessive collagen deposition with limited therapies. As a major bioactive compound in garlic, S-allyl-l-cysteine (SAC) is a neuroprotective drug candidate to prevent cognitive decline, however, its anti-pulmonary fibrotic activity remains unknown. Here, we investigated whether SAC could attenuate bleomycin (BLM)-induced pulmonary fibrosis and inflammation in mice. Our results showed that SAC dose-dependently reduced the infiltration of inflammatory cells, pulmonary lesions and collagen deposition in BLM treated mice with downregulated mRNA expression levels of fibrotic genes including alpha smooth muscle actin (α-SMA), fibronectin, collagen I and collagen III as well as the protein level of α-SMA. In addition, SAC could also reduce the mRNA expression of inflammatory mediators such as TNF-α and iNOS. Furthermore, higher phosphorylation of AKT and NF-κB p65 in IPF patient samples and murine samples was verified by immunohistochemistry while SAC could decrease the phosphorylation level of AKT and NF-κB p65 in mice stimulated with BLM. These findings, for the first time, indicate that SAC might mediate AKT/NF-κB signaling pathway to inhibit BLM-induced pulmonary fibrosis and support the potential role of SAC as an anti-pulmonary fibrosis agent.     

Genetic susceptibility in pneumoconiosis

A large number of cellular mediators such as cytokines, antioxidants and growth factors have been implicated in the pathogenesis of chronic inflammatory and fibrotic diseases. Common functional polymorphisms in these genes have been shown to influence individual susceptibility to these diseases. Silicosis, coal worker pneumoconiosis, progressive massive fibrosis and berylliosis are examples of fibrotic pneumoconiosis and are characterized by irreversible fibrotic lesions in the lung resulting from chronic dust inhalation. Although the materials are the major contributory factors of the disease pathogenesis, not all individuals exposed to similar levels develop disease. This suggests that there is a genetic predisposition to their development. Therefore, an understanding of genetic variability and the interaction between genetic and environmental factors is crucial to the identification of high-risk individuals and prevention and treatment of these diseases.     

Effect of Rho-ROCK signaling pathway on pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, reduced median survival, poor prognosis and limited therapeutic options, leading to great need for new pharmacologic therapies. In recent years, researchers have found that Rho-ROCK signaling pathway may be a new drug target in the prevention of IPF. This article reviewed the role of Rho-ROCK pathway in pulmonary fibrosis and the application of ROCK inhibitors in experimental models of IPF. Multiple lines of evidence therefore indicated that ROCK inhibition has great potential to be a powerful therapeutic tool in the prevention and treatment of IPF in clinic.     

CXCL12/CXCR4生物轴与特发性肺纤维化研究进展

特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是一种病因未明的肺间质性疾病,以肺泡上皮损伤、纤维细胞增殖、肌成纤维细胞形成、细胞外基质沉积为主要病理特征。CXCR4是纤维细胞主要的趋化因子受体,CXCL12是CXCR4的唯一配体。大量研究表明,在缺氧、HIF-1α、PI3K-Akt-mTOR路径的调节下,CXCL12/CXCR4生物轴(CXCL12/CX-CR4biological axis)能促进纤维细胞增殖、肌成纤维细胞形成、细胞外基质沉积,加速肺纤维化发病进程。该文将就CXCL12/CXCR4生物轴在特发性肺纤维化发病过程中的作用进行综述。     

Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing disease of the distal air spaces of the lung of unknown aetiology. IPF is usually fatal with a median survival of < 3 years. There are currently no effective pharmacotherapeutic agents for the treatment of IPF. In this review, unifying concepts on the pathogenesis of IPF based on understanding of host responses to tissue injury are presented. These host responses involve tightly regulated and contextually orchestrated inflammatory and repair processes. Dysregulation of either of these processes can lead to pathological outcomes. Fibrosis results from an exaggerated or dysregulated repair process that proceeds ‘uncontrolled’ even after inflammatory responses have subsided. Disease heterogeneity may arise when inflammation and repair are in different (dys)regulatory phases, thus accounting for regional disparity. Usual interstitial pneumonia (UIP), the histopathological correlate of clinical IPF, represents a more fibrotic tissue reaction pattern and for which anti-inflammatory agents are ineffective. Emerging ‘antifibrotic’ drugs and strategies for UIP/IPF are discussed. The importance of accurately phenotyping a highly heterogeneous disease process that may require individualised and ‘combined’ therapies is emphasised.     

Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing disease of the distal air spaces of the lung of unknown aetiology. IPF is usually fatal with a median survival of < 3 years. There are currently no effective pharmacotherapeutic agents for the treatment of IPF. In this review, unifying concepts on the pathogenesis of IPF based on understanding of host responses to tissue injury are presented. These host responses involve tightly regulated and contextually orchestrated inflammatory and repair processes. Dysregulation of either of these processes can lead to pathological outcomes. Fibrosis results from an exaggerated or dysregulated repair process that proceeds 'uncontrolled' even after inflammatory responses have subsided. Disease heterogeneity may arise when inflammation and repair are in different (dys)regulatory phases, thus accounting for regional disparity. Usual interstitial pneumonia (UIP), the histopathological correlate of clinical IPF, represents a more fibrotic tissue reaction pattern and for which anti-inflammatory agents are ineffective. Emerging 'antifibrotic' drugs and strategies for UIP/IPF are discussed. The importance of accurately phenotyping a highly heterogeneous disease process that may require individualised and 'combined' therapies is emphasised.     

Endothelium–platelet interactions in inflammatory lung disease

In addition to their established role in hemostasis, recent studies have identified platelets as key regulators of inflammatory reactions. Upon activation, platelets interact with both endothelial cells and circulating leukocytes. By receptor-mediated activation of interacting cell types and by release of mitogenic, pro-inflammatory and -coagulatory mediators, platelets contribute crucially to the initiation and propagation of pathological conditions and processes such as inflammatory bowel disease or atherosclerosis. In inflammatory lung disease, platelets play a critical role in the recruitment of neutrophils, eosinophils and lymphocytes as shown in experimental models of acute lung injury and allergic airway inflammation. Circulating platelet–leukocyte aggregates have been detected in patients with allergic asthma and cystic fibrosis, and in experimental lung injury. Here, we discuss the molecular mechanisms regulating the interaction of platelets with leukocytes, endothelial cells, and the subendothelial matrix with special regard to platelet kinetics in pulmonary microvessels and the putative role of platelets in inflammatory lung disorders. In light of the existing data from experimental and clinical studies it is conceivable that platelet adhesion molecules and platelet mediators provide promising targets for novel therapeutic strategies in inflammatory lung diseases.     

Endothelium-platelet interactions in inflammatory lung disease

In addition to their established role in hemostasis, recent studies have identified platelets as key regulators of inflammatory reactions. Upon activation, platelets interact with both endothelial cells and circulating leukocytes. By receptor-mediated activation of interacting cell types and by release of mitogenic, pro-inflammatory and -coagulatory mediators, platelets contribute crucially to the initiation and propagation of pathological conditions and processes such as inflammatory bowel disease or atherosclerosis. In inflammatory lung disease, platelets play a critical role in the recruitment of neutrophils, eosinophils and lymphocytes as shown in experimental models of acute lung injury and allergic airway inflammation. Circulating platelet–leukocyte aggregates have been detected in patients with allergic asthma and cystic fibrosis, and in experimental lung injury. Here, we discuss the molecular mechanisms regulating the interaction of platelets with leukocytes, endothelial cells, and the subendothelial matrix with special regard to platelet kinetics in pulmonary microvessels and the putative role of platelets in inflammatory lung disorders. In light of the existing data from experimental and clinical studies it is conceivable that platelet adhesion molecules and platelet mediators provide promising targets for novel therapeutic strategies in inflammatory lung diseases.     

Mediators of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem that is now a leading cause of death. COPD is associated with a chronic inflammatory response, predominantly in small airways and lung parenchyma, which is characterized by increased numbers of macrophages, neutrophils, and T lymphocytes. The inflammatory mediators involved in COPD have not been clearly defined, in contrast to asthma, but it is now apparent that many lipid mediators, inflammatory peptides, reactive oxygen and nitrogen species, chemokines, cytokines, and growth factors are involved in orchestrating the complex inflammatory process that results in small airway fibrosis and alveolar destruction. Many proteases are also involved in the inflammatory process and are responsible for the destruction of elastin fibers in the lung parenchyma, which is the hallmark of emphysema. The identification of inflammatory mediators and understanding their interactions is important for the development of anti-inflammatory treatments for this important disease.     

特发性肺间质纤维化的CT临床诊断回顾性队列追踪研究

目的探讨特发性肺间质纤维化CT临床诊断。方法采用流行病学回顾性队列追踪研究方法,进行个体化问卷调查表。结果 CT可见病变累及上叶和下叶,中下野明显较多,背侧更为明显,呈清晰的外周分布,重者或涉及肺中带。101例均出现清晰可见网状结节影,结节直径2～3mm,边缘模糊,网络相连。28例有明显蜂窝改变占27.72%,11例有磨玻璃改变占10.89%,13例有局限性胸膜增厚占12.87%。结论特发性肺间质纤维化（IPF）临床CT临床诊断非常重要,其肺部CT表现及病理改变为为深入和全面了解患者的治疗与转归工作提供一线临床基础资料。     

New therapeutics based on emerging concepts in pulmonary fibrosis

Introduction: Fibrosis is an irreversible pathological endpoint in many chronic diseases, including pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal condition characterized by (myo)fibroblast proliferation and transformation in the lung, expansion of the extracellular matrix, and extensive remodeling of the lung parenchyma. Recent evidence indicates that IPF prevalence and mortality rates are growing in the United States and elsewhere. Despite decades of research on the pathogenic mechanisms of pulmonary fibrosis, few therapeutics have succeeded in the clinic, and they have failed to improve IPF patient survival.

Areas covered: Based on a literature search and our own results, we discuss the key cellular and molecular responses that contribute to (myo)fibroblast actions and pulmonary fibrosis pathogenesis; this includes signaling pathways in various cells that aberrantly and persistently activate (myo)fibroblasts in fibrotic lesions and promote scar tissue formation in the lung.

Expert opinion: Lessons learned from recent failures and successes with new therapeutics point toward approaches that can target multiple pro-fibrotic processes in IPF. Advances in preclinical modeling and single-cell genomics will also accelerate novel discoveries for effective treatment of IPF.     

Heat shock protein 70 protects against bleomycin-induced pulmonary fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) involves infiltration of leucocytes, pulmonary injury, fibrosis and resulting pulmonary dysfunction. Myofibroblasts and transforming growth factor (TGF)-β1 have been suggested to play a major role in the pathology and the myofibroblasts are derived from both lung epithelial cells through epithelial-mesenchymal transition (EMT) and activation of lung fibroblasts. Heat shock protein 70 (HSP70) confers protection against various stressors and has the anti-inflammatory activity. In this study, we examined the effect of expression of HSP70 on bleomycin-induced pulmonary fibrosis in mice, a tentative animal model of IPF. Bleomycin-induced pulmonary injury and inflammatory response were ameliorated in transgenic mice overexpressing HSP70 compared to wild-type mice, even though bleomycin-induced pulmonary fibrosis and dysfunction were also suppressed in the transgenic mice. The production of TGF-β1 and expression of pro-inflammatory cytokines was lower in cells from the transgenic mice than wild-type mice after the administration of bleomycin. In vitro, the suppression of HSP70 expression stimulated TGF-β1-induced EMT-like phenotypes of epithelial cells but did not affect the TGF-β1-dependent activation of fibroblasts. Orally administered geranylgeranylacetone (GGA), a clinically used drug with HSP-inducing activity, conferred protection against bleomycin-induced pulmonary injury, as well as against the inflammatory response, fibrosis and dysfunction. These results suggest that HSP70 plays a protective role against bleomycin-induced pulmonary injury, inflammation, fibrosis and dysfunction through cytoprotective effects and by inhibiting the production of TGF-β1, TGF-β1-dependent EMT of epithelial cells and expression of pro-inflammatory cytokines. Results also suggest that HSP70-inducing drugs, such as GGA, could be beneficial in the prophylaxis of IPF.