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A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials.

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The past decade has seen substantial progress in understanding the pathobiology, natural history, and clinical significance of idiopathic pulmonary fibrosis (IPF), culminating in the establishment of two effective medical therapies. Now seems an important time to reconsider the design and conduct of future IPF clinical trials.

Building on lessons learned over the past decade, we use this perspective to lay out four key considerations for moving forward effectively and efficiently with the next generation of clinical trials in IPF. These are: development of a coordinated IPF clinical trials network; establishment of expectations for early phase proof of concept studies; adaptation of late-phase efficacy trial designs to the emergence of approved therapies, and; agreement on primary end-points for late phase clinical trials. Continued progress in the field of IPF will require creativity and collaboration on the part of all stakeholders.

We believe that addressing these four considerations will encourage and enable investment in this new era of drug development in IPF, and will lead to more rapid development of effective therapies.

Cigarette smoke alters the proteomic profile of lung fibroblasts.

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Smoking is strongly associated with diseases such as lung cancer and chronic obstructive pulmonary disease (COPD). Lung fibroblasts are crucial for the integrity of alveolar structure by producing extracellular matrix proteins which are required for attachment, structure, and function of alveolar epithelial cells. Despite the well-known association between cigarette smoke exposure and pulmonary and cardiovascular diseases, many questions remain regarding the mechanisms by which smoking induces diseases.

The aim of this study is to detect differentially expressed proteins in human foetal lung cells (HFL-1) after 5 and 10% doses of cigarette smoke extract (CSE) exposure, combining two-dimensional electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). In order to evaluate cellular ability to recover as well as lasting damage, we analysed the proteomic pattern 24 hours after the CSE removal (release). Eleven proteins had significant changes at various experimental points. Among these, 7 were up-regulated after CSE-treatments and 4 were down-regulated. Some spots seemed to be modified permanently or in a transient manner, in fact they returned to baseline levels after CSE-removal (normalisation after CSE release) and others were modified by selective CSE concentrations or only after release. MS identified, differentially expressed proteins are involved in stress response, mitochondrial activity, and aging.

These findings may improve our understanding about molecular mechanisms underlying CSE caused damage and they may also integrate the comprehension of cigarette smoke effects on human health.

HRCT of fibrosing lung disease.

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The use of high-resolution computed tomography (HRCT) has brought increased diagnostic discrimination to the evaluation of lung disease, particularly fibrosing lung diseases. Once the presence of a predominantly fibrosing lung disease has been established on evaluation of a HRCT, a stepwise approach is proposed that can refine the potential HRCT diagnoses from a list of over 100 different interstitial lung diseases to one of only five fibrosing lung diseases. Within the category of the fibrosing lung diseases, the recognition of idiopathic pulmonary fibrosis (IPF) is key.

IPF is the most prevalent idiopathic interstitial pneumonia and has a mortality greater than any of the other diffuse lung diseases. Several diagnostic dilemmas are explored including challenges with the recent IPF diagnosis and management guidelines (2011), as well as with the 'difficult to characterize' fibrosing diseases such as smoking-related lung fibrosis, unclassifiable disease and acute exacerbations of fibrosing lung disease.

The Role of Aging in Idiopathic Pulmonary Fibrosis.

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Idiopathic pulmonary fibrosis (IPF) has been gathering interest in recent years and as such this review will focus on the potential contributions that age plays on its onset and prevalence.

Environmental stress over time caused by the inhalation of foreign substances results in subsequent damage and repair of lung tissue. This damage prematurely causes a decrease in stem cell differentiation potential. In conjunction with declining proliferation, the correlation between age and general attenuation of the immune system allows for the introduction of viral components such as the Epstein-Barr virus which has been associated with lung injury, a causation which has not yet been investigated. But, regardless of environmental factors, cellular alterations due to, or in correlation with, age could result in the onset or prolonging of IPF. General genetic mutation and epigenetic methylations accumulate over a person's lifespan while miRNA expression changes from birth to adulthood. This collection of alterations over time may cause dysregulation of expressed genetic material which can result in many age-related diseases including pulmonary fibrosis.

Such alterations would be prevented by autophagy or cell-mediated apoptosis, but due to age-related dysregulations, these systems function at a diminished capacity. On the cellular level, the end result is an accumulation of dysfunctional organelles with damaged molecules, such as reactive oxygen species, and general genetic and epigenetic alterations resulting in excess generation of fibrous tissue and overall damage to the pulmonary system.

Diffuse Cystic Lung Disease: Part I.

The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous processes that are characterized by the presence of multiple spherical or irregularly shaped, thin-walled, air filled spaces within the pulmonary parenchyma. Although the mechanisms of cyst formation remain incompletely defined for all DCLDs, in most cases lung remodeling associated with inflammatory or infiltrative processes results in displacement, destruction or replacement of alveolar septa, distal airways and small vessels within the secondary lobules of the lung.

The DCLDs can be broadly classified according to underlying etiology as those due to low grade or high grade metastasizing neoplasms, polyclonal or monoclonal lymphoproliferative disorders, infections, interstitial lung diseases, smoking, and congenital or developmental defects.

In the first of a two part series, we present an overview of the cystic lung diseases caused by neoplasms, infections, smoking related diseases, and interstitial lung diseases, with a focus on lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis.

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