The overall objective of this proposal is to continue with our research on the mechanisms and physiological significance of the rapid and widespread inflammatory response to systemic hypoxia. Hypoxia occurs frequently in lung disease and is a feature of altitude exposure. Reduction of inspired oxygen levels produces mast cell activation, increased leukocyte-endothelial adhesive interactions, increased reactive oxygen species (ROS) levels, reduction in nitric oxide (NO) levels, and increased vascular permeability and leukocyte emigration. This pattern is observed in several microvascular beds, including brain, skeletal muscle and mesentery. After 3 weeks of continuous exposure to hypoxia, the initial microvascular lesion resolves, and exposure to even more severe hypoxia fails to elicit an inflammatory response, suggesting acclimatization of the microcirculation to hypoxia. The initial inflammation shares features with acute illnesses suffered by individuals ascending to altitude, and may serve as a model for these diseases.
The aims of this research, based in preliminary data obtained in our laboratory, will be to determine the mechanisms responsible for the initial microvascular response, including the possible role of a mediator substance released from a distant site to trigger the inflammation, independent of the local microvascular oxygen levels;the possible role of alveolar macrophages as the source of the putative mediator;the participation of the renin-angiotensin system (RAS) in the microvascular response to hypoxia;and the interactions between the RAS and mast cells in determining the development of hypoxia-induced inflammation. The proposed research approaches an aspect of hypoxia on which there is little information but which may have important pathophysiological implications. The research will be carried out in intact animals utilizing molecular and cellular techniques to study the microvascular response of intact animals to hypoxia. The results of pharmacological interventions will be complemented by studies in mast cell-free mice and in mice with deletion of the angiotensin converting enzyme.The scope of these studies expands from our past work in systemic oxygen transport to delve into mechanisms of oxygen transport and utilization at the tissue level and their interaction with vascular endothelial function.
|Chao, Jie; Viets, Zachary; Donham, Paula et al. (2012) Dexamethasone blocks the systemic inflammation of alveolar hypoxia at several sites in the inflammatory cascade. Am J Physiol Heart Circ Physiol 303:H168-77|
|Chao, Jie; Blanco, Gustavo; Wood, John G et al. (2011) Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia. Am J Physiol Heart Circ Physiol 301:H2264-70|
|Chao, Jie; Wood, John G; Gonzalez, Norberto C (2011) Alveolar macrophages initiate the systemic microvascular inflammatory response to alveolar hypoxia. Respir Physiol Neurobiol 178:439-48|
|Gonzalez, Norberto C; Wood, John G (2010) Alveolar hypoxia-induced systemic inflammation: what low PO(2) does and does not do. Adv Exp Med Biol 662:27-32|
|Chao, Jie; Wood, John G; Blanco, Victor Gustavo et al. (2009) The systemic inflammation of alveolar hypoxia is initiated by alveolar macrophage-borne mediator(s). Am J Respir Cell Mol Biol 41:573-82|
|Chao, Jie; Wood, John G; Gonzalez, Norberto C (2009) Alveolar hypoxia, alveolar macrophages, and systemic inflammation. Respir Res 10:54|
|Kirkton, Scott D; Howlett, Richard A; Gonzalez, Norberto C et al. (2009) Continued artificial selection for running endurance in rats is associated with improved lung function. J Appl Physiol 106:1810-8|
|Howlett, Richard A; Kirkton, Scott D; Gonzalez, Norberto C et al. (2009) Peripheral oxygen transport and utilization in rats following continued selective breeding for endurance running capacity. J Appl Physiol 106:1819-25|
|Gonzalez, Norberto C; Allen, Julie; Blanco, V Gustavo et al. (2007) Alveolar macrophages are necessary for the systemic inflammation of acute alveolar hypoxia. J Appl Physiol 103:1386-94|
|Gonzalez, Norberto C; Allen, Julie; Schmidt, Eric J et al. (2007) Role of the renin-angiotensin system in the systemic microvascular inflammation of alveolar hypoxia. Am J Physiol Heart Circ Physiol 292:H2285-94|
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