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Macrophage DAP12 pathway in emphysema

Institution: University of California, San Francisco
Investigator(s): Laura Koth, M.D.
Award Cycle: 2007 (Cycle 16) Grant #: 16RT-0072 Award: $387,237
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Smoking-related lung diseases include chronic obstructive pulmonary disease (COPD), which is comprised of emphysema, chronic bronchitis, and small airway disease. With an estimated 1.3 billion habitual cigarette smokers worldwide and 46 million adult smokers in the US it is predicted that the burden of smoking-related lung diseases will continue to grow. In the United States alone, COPD is a major public health problem affecting from 12.4 to 24 million people and is the fourth leading cause of death, accounting for approximately $6.5 billion/yr in health care expenditures. Unfortunately, there is no cure for COPD and it is likely that smoking-related lung diseases will have some impact on us all. Thus, anti-smoking measures are essential to help people to quit smoking and to prevent people from starting to smoke. However, for those people that already have lung disease and disability caused by smoking, new treatment approaches are needed to help stop the lung damage and improve respiratory symptoms. In order to develop new therapies, we need to improve our understanding of the mechanisms leading to COPD.

As a first step to generate ideas about how smoking leads to COPD, we initiated a clinical research project involving habitual cigarette smokers. The goal of our project was to identify gene expression changes in a lung cell type, the macrophage, which is thought to play a role in the development of COPD by producing mediators that cause lung inflammation and destruction. Our project involved collecting macrophages from chronic cigarette smokers, some of whom had emphysema. From these macrophages, we identified many gene expression changes that were increased in smokers, but not in nonsmokers. To our surprise many of the gene expression changes had never before been associated with COPD. It was the findings from this study that allowed us to identify a macrophage protein pathway, consisting of two proteins, called MDL-1 and DAP12, which are the focus of this application. Since these proteins had never before been associated with COPD, we performed additional studies in macrophages and found that this protein pathway appears to be affected by cigarette smoke. We also found that this pathway is necessary for the induction of an enzyme that we also found to be the third highest gene expression change in smokers’ macrophages. This enzyme, called MMP-12, is already known to cause emphysema in mice exposed to cigarette smoke and is associated with atherosclerosis.

Based on our findings, we hypothesize that cigarette smoking turns on this macrophage pathway to cause lung macrophages to produce many mediators, including MMP-12, that slowly destroy lung tissue. Thus, by blocking this pathway, we may slow down the lung destruction. In this application, we propose to study the precise mechanisms of how cigarette smoke affects this pathway, both in a cell culture system and in a mouse model. We will learn whether this pathway controls the macrophage response to cigarette smoke and whether it is a critical player in the development of emphysema.

From a public health perspective, the proposed studies are directly relevant to COPD since the proteins we are studying were identified in macrophages from habitual smokers, some of whom had COPD. This project is innovative because the pathway we are studying has never before been linked to COPD and therefore represents a new area of research in the inception and pathogenesis of COPD, but also provides new targets for medical drug therapy development. Ultimately, the goal of the proposed studies is to identify new ways to stop or decrease lung damage caused by smoking. These studies will also fill gaps in our knowledge about how cigarette smoke affects lung cells that are thought to contribute to lung disease. Through a better understanding of how cigarette smoke affects the lung cells and thereby causes cigarette smoke-induced lung inflammation and damage we can strive for better and new treatment strategies for patients that suffer from emphysema and related smoking diseases.
Publications

DAP12 is required for macrophage recruitment to the lung in response to cigarette smoke and chemotaxis toward CCL2
Periodical: Journal of Immunology Index Medicus:
Authors: Koth LL, Cambier CJ, Ellwanger A, Solon M, Hou L, Lanier LL, et al. ART
Yr: 2010 Vol: 184 Nbr: 11 Abs: Pg: 6522-8