Acute lung injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS) are a common response to many lung specific and systemic insults. The incidence of ALI/ARDS may be as high as 75 per 100,000 population annually in the USA , and mortality in this disorder remains high. During ALI and ARDS, an overlapping continuum of injury, fibroproliferation and repair exists. The lung defends itself against microbes and other injurious substances by the generation of protective innate immune responses. The lung also has a substantial capacity to repair itself and restore normal architecture following an acute injury. However, the factors which determine the severity of injury, and whether injury culminates in death, fibrosis, or repair remain unclear. Studies using animal models and in patients with ALI/ARDS have shown that a complex regulatory network of inflammatory and regulatory molecules are produced within the lung and systemically by myeloid cells, lung epithelial cells, endothelial cells, and fibroblasts. Studies performed at the University of Michigan under funding from our previous SCOR in Acute Lung Injury identified functional abnormalities that alter autocrine and paracrine regulatory loops that control inflammatory cell and fibroblast accumulation, activation, and survival, as well as host defenses against microbes. The current University of Michigan SCCOR application capitalizes on animal and clinical studies performed over the last several years of SCOR funding and have been designed studies to test the following Central Hypothesis:

Central Hypothesis

Concurrent induction of inflammatory and regulatory factors occurs in the lungs of patients with ALI/ARDS. A cytokine imbalance in these factors triggers the acute exudative phase of ALI/ARDS and creates an alveolar milieu which favors impaired pulmonary innate immune responses and fibroproliferative repair responses.