Gram-negative bacilli (GNB) are pathogens that are capable of causing severe, life-threatening pneumonia. More than 60 percent of nosocomial pneumonias are caused by GNB and associated mortality rates are often >50 percent. Over the last 10-15 years, there has been little improvement in outcome from this infection. As a result, this syndrome continues to cause significant morbidity and mortality and strongly contributes to the economic burden of our national health care system. The successful use of immune intervention in the treatment or modulation of infections has marked the beginning of a new era in the management of infectious diseases. There exists a delicate balance between an efficacious and injurious host defense response. An understanding of the host response in GNB pneumonia and how bacterial components affect this response will, in turn, lead to the development of rapid diagnostic tests that will enable the clinician to effectively utilize a variety of biologic modulators. It is also necessary to understand the relative role of bacterial components versus host factors in mediating damage to the lungs prior to therapeutic manipulations on which little is known. This information will enable us to appreciate the relative risk benefit ratio of altering the host response. Further, a more precise clarification of which host components are damaged is also needed. This knowledge may identify independent therapeutic interventions. Their global hypothesis is that surface components of GNB and/or secreted proteins differentially alter host antibacterial defenses and directly, and/or indirectly (by inflammatory mechanisms) promote lung injury. Preliminary data supports this hypothesis. These responses will have significant implications when attempting therapeutic immune interventions. The goals of this proposal are to determine the mechanisms by which the bacterial capsule and 0-specific antigen modulate neutrophil recruitment into the lungs in a diametrical manner and extend our evaluations on the relative roles of bacterial factors (e.g. hemolysin) and bacterially induced host response elements in directly mediating the pathogenesis of lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069763-04
Application #
6752790
Study Section
Special Emphasis Panel (ZRG1-SSS-W (32))
Program Officer
Harabin, Andrea L
Project Start
2001-07-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$353,250
Indirect Cost
Name
State University of New York at Buffalo
Department
Internal Medicine/Medicine
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; Beanan, Janet M; Olson, Ruth et al. (2007) A killed, genetically engineered derivative of a wild-type extraintestinal pathogenic E. coli strain is a vaccine candidate. Vaccine 25:3859-70
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
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
Raghavendran, Krishnan; Davidson, Bruce A; Helinski, Jadwiga D et al. (2005) A rat model for isolated bilateral lung contusion from blunt chest trauma. Anesth Analg 101:1482-9
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
Knight, Paul R; Davidson, Bruce A; Nader, Nader D et al. (2004) Progressive, severe lung injury secondary to the interaction of insults in gastric aspiration. Exp Lung Res 30:535-57

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