The Problem: Hospital admissions for pneumonia are increased by elevated air particle levels. The mechanism(s) underlying particle effects on lung infection are unknown, but may reflect increased incidence of infection, increased severity of infection, or both. Hypothesis: The pathogenesis of the pneumococcal pneumonia (the most common variety and the disease we will study) suggests three possible mechanisms for particle effects: enhancement of lung cell 'receptors' used by bacteria for initial adhesion, damage to antimicrobial function of host cells (AMs and PMNs), and exaggerated inflammation in established infection leading to worse signs and symptoms. Hence, the central thesis of this research is that oxidant components of air particles mediate 1) dysfunction of host defenses against infection (incidence) and 2) increased inflammation in extant pneumonia (severity). Experimental Plan:
Aim 1 will measure expression and function of pneumococcal 'receptors' (e.g., PAF receptor) used by pneumococcal for initial adhesion after exposure to concentrated ambient particles (CAPs) or control particles.
Aim 2 will determine effects of air particles on pulmonary inflammation before and after onset of pneumococcal pneumonia. The hypothesis to be tested is that particles cause enhanced release of cytokine mediators by primed AMs, leading to increased inflammation and ultimately oxidant damage to both AM and PMN In vivo and in vitro studies will measure release of pro-inflammatory cytokines, cell influx and viability and severity of pneumonic inflammation.
Aim 3 will test the hypothesis that particle exposure inhibits bacterial clearance via oxidant-dependent damage of anti-microbial functions of AMs and PMNs. Component analysis will be performed using a panel of CAPs samples to provide links of particle constituents (e.g., metals, organics, endotoxin) with biologic effects. Rotated factor analysis will be used to correlate source types with CAPs toxicity. Specific intracellular oxidant pathways will be identified by measurement of oxidant production, intracellular levels of antioxidants, and the effect of a panel of anti-oxidants and other inhibitors. Significance: This research is relevant to the public health question of how inhaled particles cause pulmonary health effects and to the pathophysiology of lung host defense against environmental agents.
| DeLoid, Glen M; Sulahian, Timothy H; Imrich, Amy et al. (2009) Heterogeneity in macrophage phagocytosis of Staphylococcus aureus strains: high-throughput scanning cytometry-based analysis. PLoS One 4:e6209 |
| Sulahian, Timothy H; Imrich, Amy; Deloid, Glen et al. (2008) Signaling pathways required for macrophage scavenger receptor-mediated phagocytosis: analysis by scanning cytometry. Respir Res 9:59 |
| Sigaud, Samuel; Goldsmith, Carroll-Ann W; Zhou, Hongwei et al. (2007) Air pollution particles diminish bacterial clearance in the primed lungs of mice. Toxicol Appl Pharmacol 223:1-9 |
| Imrich, Amy; Ning, YaoYu; Lawrence, Joy et al. (2007) Alveolar macrophage cytokine response to air pollution particles: oxidant mechanisms. Toxicol Appl Pharmacol 218:256-64 |
