title: Blockade of neutrophil responses in aspiration pneumonia via ELR-CXC chemokine antagonism does not predispose to airway bacterial outgrowth.
abstract: Pneumonia associated with aspiration of bacterial-laden gastric contents is characterized by Glu-Leu-Arg (ELR)-CXC chemokine (e.g., CXC2L1, CXCL8) expression leading to local neutrophil sequestration. This neutrophil response is designed to be protective, but overly aggressive responses can be pathogenic in themselves. Herein we assessed whether blocking neutrophil responses in a guinea pig model of aspiration pneumonia would foster airway bacterial growth. Guinea pigs (n=5) were challenged intranasally with saline, acidified saline or acidified gastric contents (35mg/kg body weight, pH 2.0) and treated subcutaneously with 250mug/kg of the human ELR-CXC chemokine antagonist CXCL8((3-72))K11R/G31P (G31P) or saline. After 20h the animals' airway inflammatory responses and bacterial burdens were assessed. A loss of vascular integrity was apparent in the lungs of the saline-treated aspiration pneumonia animals (12.07+/-1.3% of the pleural surfaces exhibited hemorrhagic consolidation, 4.6x10(6) RBC/ml bronchoalveolar lavage fluid [BALF]), as was a pulmonary neutrophilia. The BAL fluids contained gram-negative and -positive bacteria (total load, 6.3+/-3.2x10(7) CFU/ml BALF) that are associated with nosocomial infections in humans. The G31P-treatments attenuated the pulmonary vascular complications (2.27+/-0.5% pleural surface hemorrhagic consolidation, 0.46x10(6) RBC/ml BALF), and reduced the pulmonary neutrophilia by >/=86%. The G31P-treatments did not lead to significant changes in the airway bacterial loads (total load, 3.46+/-1.8x10(7) CFU/ml BALF). This data indicates that attenuation of the pulmonary neutrophil response in aspiration pneumonia reduces pathology very significantly but does not reduce the efficiency of pulmonary bacterial clearance.
authors.affiliation: Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Xixing
authors.initials: X
authors.lastname: Zhao
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Town
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhang
authors.forename: John R
authors.initials: JR
authors.lastname: Gordon
mesh_terms: D000818:Animals; D001419:Bacteria / Q000254:growth & development*; D015550:Cell Degranulation / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D008168:Lung / Q000382:microbiology* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D011015:Pneumonia, Aspiration / Q000276:immunology* / Q000382:microbiology; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D054360:Chemokine CXCL1; D016209:Interleukin-8; D012333:RNA, Messenger