Innate immune responses in the lung and liver

The innate immune system provides nonspecific defenses against pathogens. Many diseases occur because of malfunctions in the innate immune system. In the present thesis, I have investigated two independent mechanisms of innate immunity in the lung and liver. Both mechanisms involve responses to bacterial infection and/or components of the bacterial wall (lipopolysaccharide). In the first model, I studied the role of submucosal glands in lung innate immunity through the use of tracheal xenograft airways with and without glands. This work provides evidence that submucosal glands are a major source of antibacterials that are critical for maintaining sterile airways. In the second model, I studied host responses to a gram-negative bacterial cell wall component (lipopolysaccharide) and how the liver coordinates cytokine responses that lead to endotoxic shock. This work examined how hepatic induction of NFkappaB and TNFalpha influenced survival in this lethal murine model of endotoxemic shock. My findings suggest that during the course of lethal endotoxic shock, NFkappaB activation has a predominantly pro-inflammatory effect in the liver through the induction of TNFalpha, and that TNFalpha influences the role of NFkappaB as an anti-apoptotic factor in the liver. In conclusion, my thesis suggests that maintaining a homeostatic balance in response to pathogens is an important function of the complex innate immune system.