Lung inflammation

The lungs are one of the most immunologically active organs in the human body. Smoking is the major cause of obstructive airway diseases commonly termed COPD (chronic obstructive pulmonary diseases) and a major risk for lung cancers. There is still little information on the key trafficking routes and properties of particular subsets of leukocytes entering lungs during different stages of COPD. Well-controlled attenuation of leukocyte trafficking to and activation in the lungs is likely to reduce COPD progression and protect from smoke inducted lung tumorigenesis. The major aim of our studies is to identify key risk factors for COPD and identify trafficking and co-stimulatory molecules used by inflammatory leukocytes recruited to lungs that can be promising targets for anti-inflammation therapy for smokers. We have established two in vivo murine experimental models for smoke and LPS induced COPD (Movie 10). We use these models to study the roles of genetic factors that predispose mice and men to enhanced leukocyte entry into smoke triggered inflamed lungs, to augmented leukocyte effector functions, to smoke induced lung injury and to subsequent airway obstruction. We have recently unraveled major protective roles of the tumor suppressor DAPk both in the context of LPS and smoke induced lung inflammation. DAPk null mice exhibit profoundly higher sensitivity to both tobacco smoke and LPS challenges and develop a more severe COPD like disease. Notably, even after reconstitution of DAPk null mice with normal hematopoietic cells, these mice develop more severe emphysema than their WT counterparts. We conclude that DAPk is a key suppressor of lung inflammation both in innate leukocytes as well as in lung epithelial cells exposed to bacterial and tobacco smoke irritants. We are currently dissecting both the proadhesive and co-stimulatory functions of the integrin ligands ICAM-1 and ICAM-2 on multiple lung cells. These IgG superfamily cell adhesion molecules are highly abundant on both hematopoietic and non hematopoietic lung cells and play instrumental roles in leukocyte recruitment to inflamed lungs. Surprisingly, we have found a new role for these adhesion molecules in the inflammatory properties of lung alveolar macrophages. We currently investigate how macrophage activation by air-borne irritants including smoke is influenced by the activity of ICAM-1 and ICAM-2 on these leukocytes.