Explore the vast range of titles available.

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease of indeterminate etiology and limited therapeutic options. The initiation, development, and progression of IPF are influenced by genetic predisposition, aging, and host and environmental factors, but the magnitude of the contribution of each of them and the sequence of the pathogenic events are uncertain. Current evidence indicates that accumulated environmental exposures in a genetically predisposed individual, usually over 60 years of age, leads to phenotypic and functional alterations of the lung epithelium. Aberrant activation of epithelial cells results, through a complex release of numerous mediators, in the local expansion of peculiar subsets of aggressive fibroblasts and myofibroblasts, which are crucial effector cells of fibrotic remodeling and loss of the normal lung architecture and function. Progressive increase of the mechanical stiffness activates cell-autonomous and matrix-dependent processes contributing to the perpetuation of the fibrotic response. This Perspective provides an integral overview of the major risk factors underpinning the pathogenesis of IPF, including gene variants, aging alterations, environmental factors, host risk factors, and epigenetic reprogramming.

A growing body of evidence indicates that aberrant activation of alveolar epithelial cells and fibroblasts in an aging lung plays a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the biopathological processes linking aging with IPF and the mechanisms responsible for the abnormal activation of epithelial cells and fibroblasts have not been elucidated. Many of the hallmarks of aging (e.g., genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, and cellular senescence) have been proposed as essential mechanisms for the development of IPF; however, these disturbances are not restricted to IPF and also occur in other aging-related lung disorders, primarily chronic obstructive pulmonary disease (COPD). Therefore, an unanswered question is why a current/former smoker of about 60 years of age with shorter telomeres, alveolar epithelial senescence, excessive oxidative stress, and mitochondrial dysfunction develops IPF and not COPD; in other words, what makes old lungs specifically susceptible to develop IPF? In this Perspective, we propose an integral model in which the combination of some gene variants and/or gene expression in the aging lung results in the loss of epithelial integrity and consequently in the failure of the alveoli to correctly respond to injury and to face the stress associated with mechanical stretch. Afterward, a distinctive epigenetic \"reprogramming\" that affects both epithelial cells and fibroblasts provokes, among others, the recapitulation of developmental pathways and the aberrant activation and miscommunication between both cell types, resulting in the exaggerated production and accumulation of extracellular matrix and the subsequent destruction of the lung architecture.

Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating lung disorder of unknown origin, with very poor prognosis and no effective treatment. The disease is characterized by abnormal activation of alveolar epithelial cells, which secrete numerous mediators involved in the expansion of the fibroblast population, its differentiation to myofibroblasts, and in the exaggerated accumulation of extracellular matrix provoking the loss of lung architecture. Among the excessively produced mediators are several matrix metalloproteases (MMPs) which may contribute to modify the lung microenvironment by various mechanisms. Thus, these enzymes can not only degrade all the components of the extracellular matrix, but they are also able to release, cleave and activate a wide range of growth factors, cytokines, chemokines and cell surface receptors affecting numerous cell functions including adhesion, proliferation, differentiation, recruiting and transmigration, and apoptosis. Therefore, dysregulated expression of MMPs may have profound impact on the biopathological mechanisms implicated in the development of IPF. This review focuses on the current and emerging evidence regarding the role of MMPs on the fibrotic processes in IPF as well as in mouse models of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an aging-associated, progressive, and irreversible lung disease of unknown etiology, elusive pathogenesis, and very limited therapeutic options. The hallmarks of IPF are aberrant activation of alveolar epithelial cells and accumulation of fibroblasts and myofibroblasts along with excessive production of extracellular matrix. The linkage of aging with this disorder is uncertain, but a number of changes associated with aging, including telomere attrition, cell senescence, and mitochondrial dysfunction, have been revealed in IPF lungs. Also, aging seems to confer a profibrotic phenotype upon fibroblasts and to increase the severity of the fibrogenic response in non-IPF fibrotic lung disorders. Better knowledge of the pathophysiological mechanisms linking aging to IPF will advance understanding of its pathogenesis and may provide new therapeutic windows to treatment of this devastating disease.

Idiopathic pulmonary fibrosis is a devastating, age-related lung disease of unknown cause that has few treatment options. This disease was once thought to be a chronic inflammatory process, but current evidence indicates that the fibrotic response is driven by abnormally activated alveolar epithelial cells (AECs). These cells produce mediators that induce the formation of fibroblast and myofibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of the epithelial to mesenchymal transition. The fibroblast and myofibroblast foci secrete excessive amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture. The mechanisms that link idiopathic pulmonary fibrosis with ageing and aberrant epithelial activation are unknown; evidence suggests that the abnormal recapitulation of developmental pathways and epigenetic changes have a role. In this Seminar, we review recent data on the clinical course, therapeutic options, and underlying mechanisms thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis.

Key Points Idiopathic pulmonary fibrosis (IPF) is a chronic lethal lung disease, the prevalence and incidence of which dramatically increase with age. Novel therapeutic interventions for IPF are necessary as approved therapies are limited to slowing the progression of the disease. Similar to other age-related diseases, cell perturbations present in ageing cells are found in epithelial and mesenchymal cells from IPF lungs, including telomere shortening, senescence, stem cell exhaustion and mitochondrial dysfunction. The development of novel therapies for IPF has been hampered by inadequate animal models, the lack of interventions that promote epithelial repair, and the lack of understanding of the contribution of the ageing process to damage and fibrosis. Further insights into the pathogenesis of IPF, the mechanisms involved in ageing as a risk factor and the genetic predisposition to this disease are crucial to overcome current therapeutic obstacles. New therapies for idiopathic pulmonary fibrosis (IPF) are urgently needed. Here, Mora et al . discuss our current understanding of the mechanisms driving IPF, highlighting the parallels between fibrosis and ageing. Potential avenues for drug discovery and development are described, including progress made and current obstacles. Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.

Hypersensitivity pneumonitis (HP) is a complex syndrome resulting from repeated exposure to a variety of organic particles. HP may present as acute, subacute, or chronic clinical forms but with frequent overlap of these various forms. An intriguing question is why only few of the exposed individuals develop the disease. According to a two-hit model, antigen exposure associated with genetic or environmental promoting factors provokes an immunopathological response. This response is mediated by immune complexes in the acute form and by Th1 and likely Th17 T cells in subacute/chronic cases. Pathologically, HP is characterized by a bronchiolocentric granulomatous lymphocytic alveolitis, which evolves to fibrosis in chronic advanced cases. On high-resolution computed tomography scan, ground-glass and poorly defined nodules, with patchy areas of air trapping, are seen in acute/subacute cases, whereas reticular opacities, volume loss, and traction bronchiectasis superimposed on subacute changes are observed in chronic cases. Importantly, subacute and chronic HP may mimic several interstitial lung diseases, including nonspecific interstitial pneumonia and usual interstitial pneumonia, making diagnosis extremely difficult. Thus, the diagnosis of HP requires a high index of suspicion and should be considered in any patient presenting with clinical evidence of interstitial lung disease. The definitive diagnosis requires exposure to known antigen, and the assemblage of clinical, radiologic, laboratory, and pathologic findings. Early diagnosis and avoidance of further exposure are keys in management of the disease. Corticosteroids are generally used, although their long-term efficacy has not been proved in prospective clinical trials. Lung transplantation should be recommended in cases of progressive end-stage illness.

Idiopathic pulmonary fibrosis is characterized by rapid loss of vital capacity, disability, and death. There are no effective treatments. Although this study failed to meets its primary end point, the data show therapeutic efficacy at a cost of substantial GI toxicity. Idiopathic pulmonary fibrosis is a debilitating disease characterized by destruction of the gas-exchanging regions of the lung. 1 Its pathogenesis is thought to involve aberrant wound healing mediated by multiple signaling pathways, resulting in progressive lung injury and scarring. 1 Symptoms, including cough and dyspnea, limit physical activity and reduce the patient's quality of life and independence. 2 The course of the disease is difficult to predict, but it generally involves progressive deterioration, with a median survival time of 2.5 to 3.5 years after diagnosis. 3 Unpredictable acute exacerbations occur in some patients and are often fatal. 3 , 4 BIBF 1120 is a potent intracellular . . .

The authors discuss evidence suggesting that embryonic signaling pathways involved in epithelium/mesenchymal communication and epithelial cell plasticity may be aberrantly switched on in idiopathic pulmonary fibrosis.