Project D-5 will define the cellular mechanisms by which plasma leakage occurs at sites of inflammation in the airways. The studies will focus on the mechanism of formation of endothelial gaps in response to inflammatory stimuli. The long-term objective is to obtain about endothelial cells of airway blood vessels in situ that in the past has come only from studies of endothelial cells grown in vitro. The project has three specific aims: (1) The project will identify the changes in endothelial cells that occur during immediate inflammatory responses (e.g., neurogenic inflammation, resulting from substance P released from sensory nerves) in the airways of rats and determine whether the same changes occur in late-phase inflammatory responses (e.g., antigen challenge). The hypothesis to be tested is that both the immediate and the late-phase leak result from gaps between endothelial cells. The immediate leak is transient because of agonist inactivation, receptor desensitization, or other changes that lead to rapid gap resealing, but in the late-phase leak, gaps continue to form or remain open longer because the mediators have a sustained effect on the endothelium. Recently developed immunohistochemical and histochemical strategies, involving light and confocal microscopy and transmission and scanning electron microscopy, will be used to identify the leaky vessels, pinpoint the location and size of the leaky sites, quantify how rapidly leaks form and how long they last, define leak-related changes in endothelial cell shape and intercellular junctions, characterize agonist-induced changes in substance P (NK1) receptor distribution on endothelial cells, and define the relationship of pericytes and leukocytes to the sites of leakage. (2) The second aim is to determine the mechanism by which Mycoplasma pulmonis infection in rats potentiates neurogenic inflammation in the airways. The hypothesis to be tested is that M. pulmonis infection increases the sensitivity of endothelial cells to substance P by stimulating angiogenesis and by up-regulating NK1 receptor expression on endothelial cells of the newly formed blood vessels. The role of substance P-containing sensory nerves in the development of chronic inflammation induced by M. pulmonis infection will also be examined. (3) The third aim is to determine the mechanism by which anti-edema drugs reduce the sensitivity of endothelial cells to inflammatory mediators and thereby reduce plasma leakage. The hypothesis to be tested is that established anti-edema drugs such glucocorticoids and Beta2-adrenergic receptor agonists reduce plasma leakage by inhibiting the formation of endothelial gaps, but some novel anti-inflammatory peptides act through other mechanisms, such as reducing the permeability of endothelial gaps without decreasing their size. An understanding of how endothelial cells become leaky in inflammation will make it easier to develop effective strategies for reducing the plasma leakage, mucosal edema, and airflow obstruction associated with asthma and other inflammatory airway diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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