Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States, yet there are no current therapeutic treatments to halt disease progression. Airway inflammation and parenchymal destruction are central to the pathogenesis of COPD. Numerous inflammatory cell types have been implicated in COPD but an understanding of how these cell types contribute to lung destruction is lacking. Natural killer cells (NKs), an important component of the innate immune system, are known for their ability to detect and kill stressed, infected, or damaged cells. Our data demonstrate that NKs from the lungs of COPD patients are able to kill more autologous lung epithelial cells than NKs from the lungs of smokers without COPD. Similarly, in a murine cigarette smoke (CS) exposure model, lung NKs from CS-exposed mice are more cytotoxic towards autologous epithelial cells than air-exposed NKs. Therefore understanding the processes that control NK activation could identify therapeutic targets. In order to become activated, NKs undergo a priming phase, typically mediated by dendritic cells (DCs). We propose to use both human tissues and our murine CS- exposure model to demonstrate that mature DCs are necessary for NK priming. We will also investigate the mechanism of killing by focusing on the steps leading to cytotoxicity: adhesion to target cell, polarization of lytic granules, and degranulation. Finally, we will determine whether lung NK production of IL-22, a cytokine capable of inducing epithelial cells to make pro-inflammatory molecules, is also contributing to COPD pathology. To demonstrate the relevance of our findings to COPD, we also propose to study NKs and DCs from human lung tissue. Our goal is to translate results from these murine and human studies into clinically relevant discoveries regarding NK cytotoxicity in COPD pathogenesis.
COPD is currently the 3rd leading cause of death in the U.S. COPD is diagnosed in 19% of male and 17% of female VA health-care users, making COPD the fourth most common discharge diagnosis at VA hospitals. COPD causes significant morbidity and mortality and is a serious medical, financial and emotional burden on Veterans and their families. No current therapy exists to halt the progressive lung destruction of COPD. We have shown that a type of lung cell, called natural killer cells (NKs) are able to kill epithelial lung cells and that this killing is increased in COPD patients and could be contrib- uting to COPD pathogenesis. NKs also produce the protein IL-22, which can drive epithelial cells to make pro-inflammatory molecules, further contributing to COPD. This proposal will use both human lung tissue and a mouse model of cigarette smoke exposure to study NKs. The goal of this study is to identify ways to inhibit NK-mediated lung destruction that could be targeted for therapeutic benefit.
