Airway inflammation reflects a complex and orchestrated series of events, including direct- and cytokine-mediated intercellular interactions, which culminate in tissue injury and persistent airway disease. The biology that initiates and perpetuates airway disease in children is not well established. Environmental models of asthma provide an ideal opportunity to investigate the biological origin of persistent airway disease. The inflammation following respiratory challenge with grain dust (GD) elicits a spectrum of clinical responses, from acute and self-limited """"""""grain fever"""""""" to chronic airway disease Epidemiologic studies implicate chronic inhalation of grain dust is a major cause of clinically significant, irreversible airway disease in North American. Although GD is contaminated with bacterial lipopolysaccharide (LPS), not all of the observed responses are attributable to LPS. We propose studies to examine the mechanisms responsible for the initiation, promotion, and resolution of LPS/GD- induced inflammation in order to understand better the pathogenesis of asthma in children from rural communities. To this end we plan: 1. To characterize the responses of monocyte-derived macrophages (MDM) and polarized airway epithelial cells to LPS/GD (initiation); 2. To determine whether LPS/GD promotes attachment of PMNs to the basolateral surface of polarized epithelium (late initiation phase), and/or influences transmigration of PMNs across epithelial monolayers (recruitment); 3. To determine whether LPS/GD promotes attachment of PMNs to the apical surface of polarized airway epithelial cells and influences the functional status of PMNs recruited into the airway (maintenance phase); and 4. To identify the cellular responses that diminish the inflammatory cascade (resolution). Insights derived from the basic studies outlined in this project will elucidate some of the pro-inflammatory and anti-inflammatory cellular events essential for the development of environmental airway disease. The proposed studies complement the in vivo studies planned in Project 2.
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