Pseudomonas aeruginosa causes acute and chronic infections of the lung and other sites resulting in marked tissue damage. Formation of reactive oxygen species such as superoxide (O2) hydrogen peroxide (H2O2), and hydroxyl radical (OH) has been increasingly implicated in tissue injury associated with a wide array of human pathology. OH, generated via the iron (Fe)-catalyzed reaction of O2 and H2O2, is the most reactive of the oxygen free radical. Recent work from our laboratory has suggested that three compounds actively secreted by P. aeruginosa may alone, or in conjunction with neutrophil (PMN)-derived O2/H2O2, lead to OH generation and subsequent tissue injury. These P. aeruginosa-derived products are: pyochelin, a P. aeruginosa siderophore (Fe-chelator) which P. aeruginosa employs to acquire microenvironmental FE and which we found is an effective OH catalyst; pseudomonas elastase, aP. aeruginosa protease which we found cleaves the human Fe-binding protein transferrin to form new Fe chelates capable of catalyzing OH production; and pyocyanin aP aeruginosa product which can undergo cell-mediated aerobic redox cycling which results in the generation of O2 and H2O2. The goal of the work proposed is to investigate the potential specific aims have been targeted for study.
Aim 1 will assess whether the iron-pyochelin complex, ferripyochelin (Fe-derived O2 and H2O2 by inducing the generation of OH near the cell membrane.
Aim 2 will determine what oxidant species are generated during the interaction of Fe-pyochelin with O2/H2O2 what features of the pyochelin molecule serve to promote its ability to enhance O2/H2O2-cell injury, and whether a copper-pyochelin enhances pyocyanin-mediated cytotoxicity by catalyzing OH generation.
Aim 4 will determine if pseudomonas elastase cleavage of transferrin also enhances O2/H2O mediated injury of pulmonary epithelial and endothelial cells through OH catalysis.
Aim 5 will investigate whether the generation of oxidants by these P aeruginosa products alters endothelial cell function a as to further promote tissue injury by: increasing neutrophil adherence to endothelial cells by modulating the expression of adherence ligands or platelet activating factor (PAF) on the endothelial cell surface: decreasing endothelial cell prostacyclin production: or increasing endothelial cell release of pro-inflammatory cytokines such as TNF an dIL-1. Thus, these studies will explore novel and previously unexplored mechanisms whereby P. aeruginosa-derived products could contribute to lung injury by inducing the production of toxic oxygen species. Such information could eventually result in the design of new therapeutic intervention to decrease the morbidity and mortality of infections of the lung and other organs with P. aeruginosa and related bacterial pathogens.
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