We showed that the presence of elevated concentrations of IL-8 (CXCL8) bound to anti-lL-8 autoantibody (anti-lL-8:lL-8 complexes) in lung fluids is associated with progression to ARDS (acute respiratory distress syndrome), and with mortality. Although mice do not express IL-8, murine KC (CXCLI/KC) is functionally related to human IL-8. We show that anti-KC:KC complexes are present in the alveolar spaces of mice treated with lipopolysaccharide (LPS), and significantly contribute to lung inflammation and injury. Importantly, activity of anti-KC:KC complexes is mediated by receptors for IgG (FcgammaRs) because alveolar inflammatory response is substantially diminished in (-chain deficient mice (lacking stimulatory FcgammaRs). To develop a mouse model of immune complex-induced lung injury, autoantibodies to KC (in plasma and the alveolar compartment) are first induced by immunization with KC. Then, KC is administered intratracheally to generate anti-KC:KC complexes in the lung. There is a resultant influx of neutrophils, increased lung lavage protein levels, and histological evidence of lung injury in these animals. Significantly, all of these effects are dramatically suppressed in gamma-chain deficient mice. Moreover, we have already determined that Fc(Rs are the receptors involved in cellular activation mediated by anti-lL-8:lL-8 complexes in human neutrophils in vitro. Our Major Hypothesis is that IgG receptors are the predominant receptors in the lung responsible for initiating the cascade of inflammatory events triggered by anti-lL-8 autoantibody:lL-8 complexes, and that activation of IgG receptors will enhance and prolong the inflammatory response and increase the probability of acute lung injury in patients with ARDS who have anti-lL-8:lL-8 complexes. We will take two approaches to test this hypothesis. In the first 3 specific aims we will utilize human neutrophils, and in the second approach (Aim 4) we will utilize our mouse model (anti-KC:KC induced lung injury) to test our hypothesis in an animal model under controlled conditions, and to investigate potential therapeutic interventions.
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| Krupa, Agnieszka; Walencka, Maria J; Shrivastava, Vivek et al. (2007) Anti-KC autoantibody:KC complexes cause severe lung inflammation in mice via IgG receptors. Am J Respir Cell Mol Biol 37:532-43 |
| Fudala, Rafal; Krupa, Agnieszka; Matthay, Michael A et al. (2007) Anti-IL-8 autoantibody:IL-8 immune complexes suppress spontaneous apoptosis of neutrophils. Am J Physiol Lung Cell Mol Physiol 293:L364-74 |
