Mechanisms of Cigarette Smoke-Mediated Lung Inflammation in COPD

Dr. Irfan Rahman

University of Rochester , Rochester , NY

Interim Report (Last updated - March 2009)

Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States . It is a disabling condition associated with progressive breathlessness. There is no specific treatment available to stop the progression of this disease. Smoking is the main etiological factor, however, the enigma is that only 15-20% of smokers develop the disease. This in turn reflects a lack of understanding of the specific cellular and biochemical pathways triggered in the lung by tobacco smoke. The reason why only a proportion of cigarette smokers are susceptible and develop COPD is unclear at present. Cigarette smoke-triggered inflammation plays a central role in the development of COPD by a mechanism mediated via oxidant-induced enhanced pro-inflammatory gene transcription. However, little is known about the biochemical and molecular mechanism whereby cigarette smoke-mediated oxidative stress triggers lung inflammation. Histone acetylation and deacetylation comprise a key regulator of the specificity and duration of gene transcription. Alteration in the overall balance between nuclear histone acetylation: deacetylation (chromatin remodeling), and/or in acetylation patterns at specific promoters can result in aberrant transcription of pro-inflammatory genes in the lungs . The hypothesis to be tested in this proposal is that cigarette smoke and its constituents alters histone acetylation and deacetylation by p38 MAPK, mitogen and stress kinase 1 (MSK1), NF-?B-inducing kinase (NIK) and NF-kappaB signaling pathways via ROS-dependent mechanism leading to enhanced pro-inflammatory gene transcription in macrophages and in mouse lungs exposed to cigarette smoke. Increased histone acetylation is the susceptible factor for abnormal inflammation in COPD. We propose to test this hypothesis in vitro in monocytes/macrophages and in vivo in mouse lungs exposed to cigarette smoke. We focus our work on macrophages because alveolar macrophages are known to be the main orchestrators of the inflammatory response seen in lungs of patients with COPD. To test this hypothesis three specific aims are proposed: Aim 1: To understand the molecular redox signaling mechanism of histone acetylation and deacetylation in response to cigarette smoke exposure and its toxic constituents in vitro in macrophages and in vivo in mouse lungs. Aim 2: To study the inhibition of reactive oxygen species release by the use of NADPH oxidase knock-out mice (p47phox-/- and gp91phox-/-), and NIK and MSK1 KO as well as chemical inhibition of p38 MAP, NIK, MSK1 and IkappaB kinase to attenuate cigarette smoke-induced histone acetylation and pro-inflammatory cytokine release in macrophages and in lungs of mice. Aim 3: To understand the molecular mechanisms of transcriptional signaling by studying NIK and MSK1 activation, and chromatin remodeling (histone acetylation, CBP and deacetylation-sirtuin) in resected lungs obtained from smokers with and without COPD. These studies will permit identification of the underlying biochemical and molecular mechanisms whereby cigarette smoke and its toxic constituents (aldehydes/ROS) triggers cell signaling to cause abnormal lung inflammation. In this way, specific reactive components of cigarette smoke will be identified. The findings in resected human lungs from smokers with and without COPD will determine the role of histone acetylation: deacetylation, particularly sirtuin1 (an anti-inflammatory and anti-aging deacetylase) in the predisposition and susceptibility to accelerated decline in lung function or disease progression. This study will also establish an in vivo pre-clinical animal model of cigarette smoke exposure. Understanding the molecular mechanisms of lung inflammation in response to smoking and its toxicants could lead to targeted pharmacological interventions in the treatment of COPD.

TSNAs, Smokeless Tobacco, DNA Damage, Mutations, and Cancer

Dr. Timothy O'Connor

City of Hope National Medical Center , Duarte , CA

Interim Report ( Last updated -)

Receptor-Mediated Mechanisms of Tobacco-Induced Lung Oncogenesis

Dr. Sergie Grando

University of California at Irvine , Irvine , CA

Interim Report ( Last updated -)

DNA Repair Activity in Human Lung Tissue as a Possible Marker for Individual Response to Tobacco Smoke Constituents

Dr. Judith Zelikoff Foth

New York University School of Medicine, Tuxedo, NY