PULMONARY IMMUNE ENVIRONMENT DETERMINES THE MANIFESTATION OF EXPERIMENTAL EMPHYSEMA

The lung is a complex well-designed organ providing a large surface area for exchanging gas to provide oxygen to the body and eliminate carbon dioxide from the circulation. Because of its exposure to the environment, it is required to have active immunologic defense mechanisms to remove hazardous agents and maintain homeostasis. However, an aberration in this pulmonary immune environment can lead to several pathologic developments. Emphysema is characterized by progressive loss of alveolar surface area with a permanent airspace enlargement, and it is one of the major public health issues leading to serious morbidity and mortality. Disparities in individual immune responses interact with host genetic predispositions and environmental factors in a complex manner that impacts the susceptibility to develop emphysema. The overall goal of this thesis was to study immunological factors that are involved in determining the susceptibility to develop emphysema using a simplified elastase-induced murine model. First, we determined the susceptibility to develop emphysema in two common strains of mice. We found BALB/cJ mice to be much more sensitive to exogenous elastase compared to C57BL/6J mice. Based on gene expression analysis, we found different immunologic mechanisms that might underlie the differential progression of elastase-induced emphysema in these two mouse strains. In addition, MMP-producing macrophages (but not neutrophils or lymphocytes) were identified as the critical cells that mediate the extracellular matrix degradation in emphysema. Furthermore, we use genetically engineered mice to study the importance of several cytokine signaling pathways and transcription factors. We found important roles of IL-17A, IFN-, IL-33/ST2/MyD88, STAT6 and STAT3 in activating or modulating the macrophages to become more destructive. Lastly, we also showed that recent viral infections could impact on the severity of emphysema following the acute elastase injury. In conclusion, the intricacy of genetic and environmental factors together influence immune responses in the lungs to determine the susceptibility to develop emphysema. This knowledge provides new insights into the cellular and molecular mechanisms that may be responsible for the heterogeneity observed in human susceptibility to develop emphysema