Cigarette smoke-induced proteostasis imbalance in obstructive lung diseases.

Curr Mol Med. 2012 Jun 5;

Authors: Cantin AM, Richter MV

Abstract
The airway and alveolar surface is exposed daily to 8,000 L of air containing oxygen, particles, bacteria, allergens and pollutants, all of which have the potential to induce oxidative stress within cells. If one is also a cigarette smoker, then the exposure to reactive oxidants increases exponentially. More than any other tissue, the lung is at risk of undergoing oxidative changes in protein expression, structure and function. The oxidant burden of chronic cigarette smoke exposure can overwhelm the lung cells� capacity to maintain proteostasis, a process of regulated protein synthesis, folding and turnover. Somewhat surprisingly, most chronic cigarette smokers do not develop chronic obstructive pulmonary disease (COPD), likely because cells initiate a highly effective unfolded protein response (UPR) in the presence of oxidant-derived endoplasmic reticulum (ER) stress that allows cells to survive. The UPR initiates several signaling pathways that decrease protein translation, limit cell cycle progression, increase protein degradation and chaperone-mediated protein folding, and activate the transcription factor Nrf2 that induces antioxidant gene expression. Each of these actions decreases ER stress in a process of "healthy proteostasis". If these responses are insufficient, apoptosis ensues. In this article, we review the mechanisms of healthy and dysfunctional proteostasis related to cigarette smoke exposure and COPD.

PMID: 22697342 [PubMed - as supplied by publisher]

Proteostasis, an Emerging Therapeutic Paradigm for Managing Inflammatory Airway Stress Disease.

Curr Mol Med. 2012 Jun 5;

Authors: Bouchecareilh M, Balch WE

Abstract
Airways stress diseases (ASDs), including chronic obstructive pulmonary (COPD) disease, emphysema and asthma, are predicted to become the third leading cause of morbidity and mortality by 2020. An understanding and the treatment of these diseases will have a high impact on human health and the health system. An emerging area of heathspan impact is the link between ASDs and proteome homeostasis or 'proteostasis', a biological system comprised of >2000 components that direct the generation, maintenance and removal of proteins to achieve normal function. Alpha-1 antitrypsin deficiency (αA1TD) aggregates activating extracellular folding stress pathways, dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and misprocessing by acetyltransferase (HAT)/histone deacetylase (HDAC) pathways represent key examples of proteostasis imbalance involved in ASDs. Common to these events in the lung is a chronic inflammatory response in response to NF-κB signaling and protein folding stress associated with an excess of mucus secretion, tissue remodeling, peribronchiolar fibrosis, bronchoconstriction and aveolar destruction. All of these emergent properties of disease are a consequence of imbalance in the proteostasis system. Herein, we discuss the role of proteostasis and its consequences on lung pathophysiology in inflammatory ASD, and suggest how manipulating the proteostasis network through pharmacological intervention of proteostasis pathways could provide multiple routes for the restoration of lung physiology.

PMID: 22697348 [PubMed - as supplied by publisher]

Related Articles

Serologic evaluation in idiopathic interstitial pneumonias.

Curr Opin Pulm Med. 2012 Jun 13;

Authors: Papiris SA, Kagouridis K, Bouros D

Abstract
PURPOSE OF REVIEW: Diagnosis of idiopathic interstitial pneumonias (IIPs) requires the exclusion of, among others, concomitant connective tissue diseases (CTDs), which may present as interstitial lung disease (ILD). This review focuses on the evaluation required to separate these entities through serology, although not exclusively. RECENT FINDINGS: Several recent data suggest that patients diagnosed with IIPs can show evidence of CTDs on follow-up. This is especially true for nonspecific interstitial pneumonia but may also be seen with other forms of ILD. SUMMARY: ILDs may occur alone, IIPs, or in association with, among others, CTDs. In the latter case, they may present before, during or even several months or years after the fulfillment of undisputed criteria for CTDs. If present before, their presentation presupposes their occurrence in early undiagnosed, undefined or undifferentiated CTD, which occasionally indefinitely maintains this status of diagnostic uncertainty, especially if ILD is empirically treated by immunosuppressants. Serologic evaluation for autoantibodies assisted by serum inflammatory biomarkers, detailed search for clinical clues of CTDs and suggestive histopathologic features on lung specimens may provide a framework to build the correct diagnosis. Obtaining a diagnosis of ILD associated with CTD exceeds semantics as this subset of patients may present different natural history, pathobiology, treatment and prognosis.

PMID: 22699420 [PubMed - as supplied by publisher]

Related Articles

Simvastatin reduces endotoxin-induced acute lung injury by decreasing neutrophil recruitment and radical formation.

PLoS One. 2012;7(6):e38917

Authors: Grommes J, Vijayan S, Drechsler M, Hartwig H, Mörgelin M, Dembinski R, Jacobs M, Koeppel TA, Binnebösel M, Weber C, Soehnlein O

Abstract
INTRODUCTION: Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions.
METHODS: C57Bl/6 mice were exposed to aerosolized LPS (500 µg/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice.
RESULTS: Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance.
CONCLUSION: Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI.

PMID: 22701728 [PubMed - in process]