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Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations  [PDF]
Alberto Diaz de Leon,Jennifer T. Cronkhite,Anna-Luise A. Katzenstein,J. David Godwin,Ganesh Raghu,Craig S. Glazer,Randall L. Rosenblatt,Carlos E. Girod,Edward R. Garrity,Chao Xing,Christine Kim Garcia
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010680
Abstract: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations.
The role of integrins in pulmonary fibrosis
D. Sheppard
European Respiratory Review , 2008,
Abstract: Integrins are a large family of transmembrane glycoprotein receptors initially identified as mediators of cell adhesion and tissue integrity. However, it is now known that the primary function of integrins in mammals is to act as signalling proteins. Signals from integrins are known to play critical roles in virtually every aspect of the behaviour of epithelial cells and in the development of certain pathological conditions, including pulmonary fibrosis. In this respect, the interaction between transforming growth factor-β, which is known to be pivotal in the development of pulmonary fibrosis, and the integrin alphaVβ6 is of particular interest. Integrin alphaVβ6 is responsible for the activation of constitutively expressed latent transforming growth factor-β by a mechanism that allows for temporal and spatial activity control. There is increasing evidence that this mechanism plays a critical role in the pathological activity of transforming growth factor-β. Although other activation mechanisms have been identified, studies suggest that alphaVβ6-mediated activation of transforming growth factor-β is necessary for the development of fibrosis in lung-disease models. The data from such studies imply that integrins may be attractive targets for intervention in pulmonary fibrotic diseases, such as idiopathic pulmonary fibrosis.
Molecular and cellular mechanisms of pulmonary fibrosis
Nevins W Todd, Irina G Luzina, Sergei P Atamas
Fibrogenesis & Tissue Repair , 2012, DOI: 10.1186/1755-1536-5-11
Abstract: Pulmonary fibrosis is a chronic lung disease characterized pathologically by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture, and additionally characterized by recognizable clinical, physiologic, and radiographic findings. Though some descriptions of fibrous diseases of the lungs can be found as early as the 5th century BC by Hippocrates [1,2], more modern descriptions of pulmonary fibrosis occurred in the early part of the 20th century with reports by Hamman and Rich of four patients with rapidly progressive diffuse interstitial fibrosis of the lungs [3,4]. Although the prognosis of patients with diffuse pulmonary fibrosis is poor, it was subsequently realized that many patients did not have the extremely rapid deteriorating course that was described by Hamman and Rich. With further pathologic analysis, several distinct types of pulmonary fibrosis were described, and the terms diffuse fibrosing alveolitis, diffuse interstitial fibrosis, and idiopathic pulmonary fibrosis (IPF) were introduced to describe a more insidious, yet still debilitating form of chronic pulmonary fibrosis [5,6]. Currently, IPF is considered the most common and severe form of pulmonary fibrosis, with a disheartening median survival of approximately three years, with no proven effective therapy, and with lung transplantation remaining the only viable intervention in end-stage disease [7].The pathologic findings in pulmonary fibrosis (excessive accumulation of ECM and remodeling of the lung architecture) are a consequence of disturbances in two physiologically balanced processes: proliferation and apoptosis of fibroblasts, and accumulation and breakdown of ECM. When the normal balance between ECM deposition and turnover is shifted toward deposition or away from breakdown, excessive ECM accumulates. When the balance between fibroblast proliferation and apoptosis is shifted toward accelerated proliferation or slowed apoptosis, fibroblasts - the primary
The role of apoptosis in pulmonary fibrosis
B. D. Uhal
European Respiratory Review , 2008,
Abstract: Apoptosis has been defined as "gene-directed cellular self-destruction" and is an active process that is tightly regulated by a number of gene products, which promote or block cell death. Apoptotic death can be triggered by a wide variety of stimuli and, importantly, not all cells necessarily undergo apoptosis in response to the same stimulus. Abnormal regulation of apoptosis has been implicated in a wide range of diseases and approaches to modifying apoptosis represent important future therapeutic strategies. Idiopathic pulmonary fibrosis (IPF) is a progressive and relentless disease involving scarring of the lung, which has been recognised as the most lethal interstitial lung disease. In the lungs of IPF patients, increased epithelial apoptosis, together with decreased apoptosis of myofibroblasts, represents persistent findings (particularly in areas of collagen deposition) supporting an interaction between altered apoptosis and the pathogenesis of the disease. Data from human tissues and animal models are refining current knowledge of the processes involved in this pathogenesis. This has challenged the dogma that IPF is purely a disease of unresolved inflammation by emphasising the central roles played by the alveolar epithelial cell and myofibroblasts and, as part of that role, the importance of altered apoptosis. Evidence suggests blockade of epithelial cell apoptosis can prevent subsequent collagen deposition, and induction of myofibroblast apoptosis, at least theoretically, would be expected to resolve ongoing fibrosis. These two concepts raise the prospect of therapeutic intervention aimed at modifying apoptosis and, thus, fibrosis in idiopathic pulmonary fibrosis.
Epithelial fibroblast triggering and interactions in pulmonary fibrosis
P. W. Noble
European Respiratory Review , 2008,
Abstract: Idiopathic pulmonary fibrosis (IPF) is characterised by repeated injury to the alveolar epithelium with loss of lung epithelial cells and abnormal tissue repair, resulting in excessive accumulation of fibroblasts and myofibroblasts, deposition of extracellular matrix components and distortion of lung architecture, eventually leading to respiratory failure. There is growing circumstantial evidence to suggest that in IPF the alveolar epithelium is prone to undergoing programmed cell death following repeated injury, although the mechanism for inducing epithelial apoptosis is, as yet, unknown. Potentially, one explanation may be the formation of misfolded proteins and an unfolded protein response-mediated apoptosis in alveolar epithelial cells (AECs), in response to abnormal protein production and aggregation. Epithelial apoptosis is accompanied by damage to the basement membrane leading to the release of growth factors and chemokines, which recruit fibroblasts to the site of injury (fibroblastic foci). Instead of AECs healing by repair, myofibroblast proliferation and extracellular matrix deposition continues unabated in IPF. The transformation of epithelial cells into mesenchymal cells, a process known as epithelial-mesenchymal transition, which allows direct communication between cells, is a possible explanation for the activation of alveolar epithelial cells in idiopathic pulmonary fibrosis. The present article discusses this process and other potential mechanisms by which epithelial cell injury can lead to fibroblast recruitment and accumulation in idiopathic pulmonary fibrosis.
Angiotensinogen Gene Transcription in Pulmonary Fibrosis  [PDF]
Bruce D. Uhal,My-Trang T. Dang,Xiaopeng Li,Amal Abdul-Hafez
International Journal of Peptides , 2012, DOI: 10.1155/2012/875910
Abstract: An established body of literature supports the hypothesis that activation of a local tissue angiotensin (ANG) system in the extravascular tissue compartment of the lungs is required for lung fibrogenesis. Transcriptional activation of the angiotensinogen (AGT) gene is believed to be a critical and necessary step in this activation. This paper summarizes the data in support of this theory and discusses transcriptional regulation of AGT, with an emphasis on lung AGT synthesis as a determinant of fibrosis severity. Genetic data linking AGT polymorphisms to the severity of disease in Idiopathic Pulmonary Fibrosis are also discussed. 1. Introduction Pulmonary fibrosis results from injury to the lung and an ensuing fibrotic response that leads to thickening of the alveolar walls and the obliteration of alveolar air spaces. If the etiology is unknown, the condition is designated as idiopathic pulmonary fibrosis (IPF) [1]. There are also several groups of xenobiotics or environmental toxins known to cause pulmonary fibrosis, for example, the antineoplastic agent bleomycin, the class III antiarrhythmic agent amiodarone, gamma-irradiation, silicon dust, and asbestos [2]. The main histological features of the fibrotic lung are persistent and unrepaired epithelial damage, proliferation and accumulation of fibroblasts and myofibroblasts, and increased collagen deposition [3]. This section will discuss evidence that lung-derived angiotensinogen (AGT) plays an important role in lung fibrogenesis. 2. Lung-Derived AGT in Lung Fibrogenesis Numerous studies support the existence of “local” angiotensin (ANG) systems in various organs and tissues. For example, the ANG II concentrations in the interstitial compartment of heart and eye were found to be 5–100 fold higher (about 50–500?pM) than that in plasma (~5–10?pM) [4, 5]. The higher interstitial levels of ANG II compared to the circulating level could not be explained by diffusion and/or receptor-mediated uptake of circulating angiotensin II. These results thereby suggest that tissue angiotensin II is largely, if not completely, synthesized locally. Furthermore, cultured cells from various organs including heart [6], vascular endothelium [7], brain [8–10], and lung [11] were shown to express the ANG system components such as AGT, ANG II, and their corresponding converting enzymes and angiotensin receptors. In contrast to the classical endocrine “renin-angiotensin-aldosterone system” (RAAS) in which the octapeptide angiotensin II is enzymatically cleaved from AGT by the actions of renin and angiotensin-converting enzyme
Idiopathic pulmonary haemosiderosis with mineralizing pulmonary elastosis: A case report
Amanjit Bal, Ashish Bhalla, Kusum Joshi
Journal of Medical Case Reports , 2008, DOI: 10.1186/1752-1947-2-65
Abstract: The case presented here is of an adult man with idiopathic pulmonary haemosiderosis with mineralizing pulmonary elastosis.Pathologists are generally not familiar with this histologic reaction pattern associated with iron encrustation of pulmonary elastic tissue.Diffuse pulmonary haemosiderosis is characterized by repeated episodes of intra-alveolar haemorrhage leading to abnormal accumulation of iron as haemosiderin in alveolar macrophages with subsequent pulmonary fibrosis and severe anaemia [1,2]. Pulmonary haemosiderosis (PH) occurs either primarily as a disease of the lungs or secondary to systemic diseases. Idiopathic PH, first described by Ceelen in 1931, is characterized by a clinical triad of haemoptysis, anaemia and pulmonary infiltrates. Eighty percent of cases of PH occur in children [2]. We report a case of an adult man with idiopathic PH with mineralizing pulmonary elastosis.A 32-year-old, non-smoking, male farmer presented with a history of fever, intermittent episodes of mild haemoptysis and cough with expectoration for the previous six months. There was associated loss of appetite and loss of weight. He started experiencing respiratory distress 8 days prior to hospital admission. Two years earlier he was diagnosed with pulmonary tuberculosis based on X-ray findings whereupon he was commenced on anti-tubercular treatment, however the level compliance is not known. On physical examination his respiratory rate and jugular venous pressure were elevated, and he had clubbing. On chest auscultation there were bilateral coarse crepitations. Pulmonary function tests were consistent with restrictive ventilatory defect. Laboratory investigations revealed iron deficiency anaemia and there were negative results for antinuclear antibodies (ANA) and antineutrophilic cytoplasmic antibodies (ANCA). On ultrasound examination of the abdomen there was evidence of hepatosplenomegaly. The clinical impression was of disseminated tuberculosis. The patient was placed on ambu
Smoking and Pulmonary Fibrosis: Novel Insights  [PDF]
Katerina D. Samara,George Margaritopoulos,Athol U. Wells,Nikolaos M. Siafakas,Katerina M. Antoniou
Pulmonary Medicine , 2011, DOI: 10.1155/2011/461439
Abstract: The relationship between smoking and pulmonary fibrosis is under debate and intense investigation. The aim of this paper is to review the existing literature and identify further areas of research interest. Recently the negative influence of cigarette smoking on IPF outcome was highlighted, as non-smokers exhibit a better survival than ex-smokers and combined current- and ex-smokers. In patients with non-specific interstitial pneumonia (NSIP), a high prevalence of emphysema was recently demonstrated, providing an indirect support for a smoking pathogenetic hypothesis in NSIP. The coexistence of pulmonary fibrosis and emphysema has been extensively described in a syndrome termed combined pulmonary fibrosis and emphysema (CPFE). Connective tissue disorders (CTDs) are a group of autoimmune diseases which affect the lung, as one of the most common and severe manifestations. However, the relationship between smoking and autoimmune disorders is still conflicting. Rheumatoid arthritis results from the interaction between genetic and environmental factors, while the best established environmental factor is tobacco smoking. Smoking has also a negative impact on the response of the RA patients to treatment. The aforementioned smoking-related implications give rise to further research questions and certainly provide one more important reason for physicians to advocate smoking cessation and smoke-free environment. 1. Introduction Smoking is one of the most prevalent and addictive habits, affecting billions of people and influencing their behaviour. The health risks and effects of tobacco smoking are well known, and their span affects multiple systems of the human body. The direct pathogenetic relationship between cigarette smoking and certain respiratory diseases such as emphysema, chronic obstructive pulmonary disease (COPD), and lung cancer is well documented [1]. Regarding interstitial lung damage there is strong evidence providing links with cigarette smoking. Smoking has been identified as a causative agent in some diffuse parenchymal diseases like respiratory bronchiolitis-interstitial lung disease (RB-ILD) and desquamative interstitial pneumonia (DIP). These diseases have a fairly good prognosis following smoking cessation and treatment [2]. However the relationship between smoking and IPF, the idiopathic interstitial pneumonia with the worst overall prognosis and survival, is under debate, intense research, and investigation. The aim of this paper is to review the existing literature and identify further areas of research interest. 2. Idiopathic
Soluble TNF Mediates the Transition from Pulmonary Inflammation to Fibrosis  [PDF]
Nikos Oikonomou, Vaggelis Harokopos, Jonathan Zalevsky, Christos Valavanis, Anastasia Kotanidou, David E. Szymkowski, George Kollias, Vassilis Aidinis
PLOS ONE , 2006, DOI: 10.1371/journal.pone.0000108
Abstract: Background Fibrosis, the replacement of functional tissue with excessive fibrous tissue, can occur in all the main tissues and organ systems, resulting in various pathological disorders. Idiopathic Pulmonary Fibrosis is a prototype fibrotic disease involving abnormal wound healing in response to multiple sites of ongoing alveolar epithelial injury. Methodology/Principal Findings To decipher the role of TNF and TNF-mediated inflammation in the development of fibrosis, we have utilized the bleomycin-induced animal model of Pulmonary Fibrosis and a series of genetically modified mice lacking components of TNF signaling. Transmembrane TNF expression is shown to be sufficient to elicit an inflammatory response, but inadequate for the transition to the fibrotic phase of the disease. Soluble TNF expression is shown to be crucial for lymphocyte recruitment, a prerequisite for TGF-b1 expression and the development of fibrotic lesions. Moreover, through a series of bone marrow transfers, the necessary TNF expression is shown to originate from the non-hematopoietic compartment further localized in apoptosing epithelial cells. Conclusions These results suggest a primary detrimental role of soluble TNF in the pathologic cascade, separating it from the beneficial role of transmembrane TNF, and indicate the importance of assessing the efficacy of soluble TNF antagonists in the treatment of Idiopathic Pulmonary Fibrosis.
Abnormal wound healing responses in pulmonary fibrosis: focus on coagulation signalling
R. C. Chambers
European Respiratory Review , 2008,
Abstract: The normal response of tissue to injury involves a sequence of overlapping events, which need to occur in a timely and controlled manner for successful tissue repair and restoration of normal function. Failure to control the healing process can lead to considerable tissue remodelling and the replacement of functional tissue with permanent fibrous scar tissue. It is proposed that pulmonary fibrosis arises from repetitive, widespread epithelial injury. However, the nature of the insult for the most common and most fatal form of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), is currently unknown and the pathogenetic pathways leading to IPF remain to be fully elucidated. Increasing evidence suggests that abnormalities in a number of pathways involved in the wound healing response may play central roles. The present article will briefly review the pathways involved in wound healing focusing on the control of fibroblast/myofibroblast function and the coagulation cascade acting via the family of signalling receptors, the proteinase activated receptors, which influence a range of cellular responses implicated in the development of pulmonary fibrosis. Understanding the involvement of these pathways in the aberrant wound repair-response in pulmonary fibrosis may lead to the identification of new targets and strategies for therapeutic intervention.
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