The lung displays a complex inflammatory response to a variety of antigenic challenges. This immune response is critical to host survival by facilitating pathogen clearance and maintaining lung homeostasis. Dysregulation of this response can lead to an over- exuberant proinflammatory response resulting in acute lung injury. Conversely, the inability to mount adequate inflammation may hinder pathogen clearance. An improved understanding of the key regulators of innate pulmonary inflammation remains an important goal in understanding the pathophysiology of lung injury and in identifying innovative therapeutic strategies. We have identified interleukin-10 as a crucial endogenous regulator of lung inflammation on the basis of its ability to inhibit cytokine expression. Because of this potent anti-inflammatory property, we hypothesize that the level of lung-specific IL-10 expression is a key modulator of host innate and acquire immune responses. In order to test this hypothesis, we propose to use a well-characterized model of adenoviral triggered inflammation in mice with genetically altered levels of IL-10 expression. A summary of the proposed aims are: 1) To determine the effect of tonic levels of lung-specific IL-10 on alveolar macrophage phenotype and function, 2) To define the role of IL-10 in regulating lung leukocyte trafficking following adenoviral infection in vivo, and 3) To determine if overexpression of IL-10 preserves surfactant protein production and function following adenoviral infection and may alter the state of diiferentiation of the respiratory epithelium. These studies will provide unique insight into the role of IL-10 in regulating the lung's innate and acquired immune responses. The principle investigator is Assistant Professor of Pediatrics in Critical Care Medicine. The Mentored Clinical Scientist Development Award will allow him to continue his development as a clinician-scientist. There is a productive research environment at the Children's Hospital Research Foundation with a number of investigators utilizing transgene strategies to address both lung development and the lung response to inflammatory challenges. The experimental design contains challenging goals with anticipated completion of the aims within three years. The information may identify a means to modulate pulmonary inflammation in patients and identify novel biologic effects of IL-10 on viral-mediated inflammatory responses.
