Anesthesia/surgery predisposes the patient to develop nosocomial pneumonia by mechanisms that are not completely defined. The presence of a viral respiratory tract infection (RTI) during anesthesia/surgery further complicates the host antibacterial response. Evidence from our laboratory has demonstrated anesthesia/surgery induces changes in cytokine response (e.g., TNFalpha, MIP-2, IFNgamma), leukocyte recruitment, and lung injury to influenza RTI. These responses are also critical to innate host defenses against bacterial pathogens. Our focus is to examine cellular mechanisms during a viral RTI that predispose the host to a post-surgical bacterial pneumonia. We hypothesize that anesthesia/surgery will change host responses differently during distinct periods in the course of a viral RTI by altering expression of pro- and antiinflammatory cytokines, thereby decreasing antibacterial defenses.
Aim #1 will assess the effects of anesthesia/surgery during influenza on bacterial clearance, inflammatory cell influx, and cytokine expression an Escherichia coli challenge. We predict that laparotomy during influenza will promote the relative expression of MCP-1 and IL-10 over TNFalpha, MIP-2, and IFNgamma.
Aim #2 : will assess ex vivo the combined effect of laparotomy and influenza on a) LPS stimulated aMphi cytokine expression and phagocytic activity, and b) the ability of in vitro antiMCP-1, antiIL-10, or IFNgamma administration to improve M dysfunction. We postulate that laparotomy during influenza will alter aMphi regulatory functions and decrease effector functions as a result of selective enhancement of expression anti-compared to proinflammatory cytokines. Finally, in Aim #3, we will examine the contribution of endogenous cytokines in the suppression of antibacterial defenses following laparotomy during influenza by selective cytokine manipulations. Bacterial clearance, inflammatory cell influx, and cytokine levels will be assessed. We anticipate that neutralization of IL-10 or MCP-1, administration of IFNgamma, or increased TNFalphaexpression will improve antibacterial host defenses following laparotomy during physical signs of influenza. These studies will examine mechanisms that lead to alterations in bacterial clearance post-surgically following a viral RTI, assess the pathogenesis of post-surgical pneumonia in general, and suggest immune adjuvant strategies to prevent this complication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046534-05
Application #
6896250
Study Section
Special Emphasis Panel (ZRG1-SSS-W (37))
Program Officer
Korpela, Jukka K
Project Start
2001-07-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2007-05-31
Support Year
5
Fiscal Year
2005
Total Cost
$392,500
Indirect Cost
Name
State University of New York at Buffalo
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Russo, Thomas A; Davidson, Bruce A; Beanan, Janet M et al. (2007) Capsule and O-antigen from an extraintestinal isolate of Escherichia coli modulate cytokine levels in rat macrophages in vitro and in a rat model of pneumonia. Exp Lung Res 33:337-56
Russo, Thomas A; Wang, Zhengdong; Davidson, Bruce A et al. (2007) Surfactant dysfunction and lung injury due to the E. coli virulence factor hemolysin in a rat pneumonia model. Am J Physiol Lung Cell Mol Physiol 292:L632-43
Segal, Brahm H; Davidson, Bruce A; Hutson, Alan D et al. (2007) Acid aspiration-induced lung inflammation and injury are exacerbated in NADPH oxidase-deficient mice. Am J Physiol Lung Cell Mol Physiol 292:L760-8
Hutson, Alan D; Davidson, Bruce A; Raghavendran, Krishnan et al. (2006) Statistical prediction of the type of gastric aspiration lung injury based on early cytokine/chemokine profiles. Anesthesiology 104:73-9
Russo, Thomas A; Davidson, Bruce A; Genagon, Stacy A et al. (2005) E. coli virulence factor hemolysin induces neutrophil apoptosis and necrosis/lysis in vitro and necrosis/lysis and lung injury in a rat pneumonia model. Am J Physiol Lung Cell Mol Physiol 289:L207-16
Davidson, Bruce A; Stewart, Carleton C; Russo, Thomas A et al. (2005) Discrimination of resident and infiltrated alveolar macrophages by flow cytometry in influenza A virus-infected mice. Exp Lung Res 31:323-39
Ignatowski, Tracey A; Sud, Reeteka; Reynolds, Jessica L et al. (2005) The dissipation of neuropathic pain paradoxically involves the presence of tumor necrosis factor-alpha (TNF). Neuropharmacology 48:448-60
Raghavendran, Krishnan; Davidson, Bruce A; Mullan, Barbara A et al. (2005) Acid and particulate-induced aspiration lung injury in mice: importance of MCP-1. Am J Physiol Lung Cell Mol Physiol 289:L134-43
Davidson, Bruce A; Knight, Paul R; Wang, Zhengdong et al. (2005) Surfactant alterations in acute inflammatory lung injury from aspiration of acid and gastric particulates. Am J Physiol Lung Cell Mol Physiol 288:L699-708
Rotta, Alexandre T; Shiley, Kevin T; Davidson, Bruce A et al. (2004) Gastric acid and particulate aspiration injury inhibits pulmonary bacterial clearance. Crit Care Med 32:747-54

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