Lung inflammation contributes to morbidity in critically ill patients, including those with Acute Respiratory Distress Syndrome (ARDS). Pulmonary surfactant-associated proteins are emerging as important modulators of host defense and alveolar inflammation, in addition to their role in reducing alveolar surface tension. Lung inflammation is characterized by elevated neutrophil and interleukin-8 (IL-8) concentrations in BAL fluid from patients with ARDS. Chemokines, such as IL-8, are potent endogenous neutrophil chemoattractants and are also elevated in BAL fluid from ARDS patients. In addition, lipopolysaccharide (LPS) and lipopolysaccharide-binding protein (LBP) are important mediators of inflammatory responses in the lung. The major goals of this proposal are to elucidate the mechanisms by which surfactant proteins inhibit alveolar inflammation and to determine what role this may play in ARDS patients. My hypothesis is that surfactant proteins bind LPS, blocking the interaction of LPS and LBP, thus inhibiting alveolar inflammation. Furthermore, I postulate that surfactant proteins can bind chemokines and inhibit their proinflammatory effects in the alveolar air space during acute lung injury. I hypothesize SP-A and SP-B levels will predict outcome in patients who are at-risk for developing ARDS and be potentially useful clinical markers.
The specific aims of this proposal are: (l) To measure SP-A and SP-B levels in the blood and BALF of patients with ARDS, during their at-risk period and serially after the development of ARDS. Measures of outcome will include development of ARDS, lung injury score, and mortality. (2) To investigate whether SP-A or SP-B alters the interaction between LPS, soluble LPS-binding proteins present in the alveoli, and target effector cells in the lung. My preliminary data suggest that SP-A inhibits LPS/LBP induced IL-8 production in THP-1 cells. I will also examine the interaction between SP-A and LPS/LBP in human alveolar macrophages. (3) To examine if SP-A is able to bind to and modulate the effects of inflammatory chemokines found in BAL fluid during acute lung injury. I will study the interaction between SP-A and specific chemokines like lL-8. My preliminary data show that SP-A inhibits IL-8 induced PMN chemotaxis. I will study the mechanisms by which SPA blocks the proinflammatory effects of IL-8. These studies combine clinically oriented studies in patients with ARDS with basic studies of new mechanisms by which surfactant proteins may modulate inflammation in the lung.
