title: Platelet-activating factor receptor plays a role in lung injury and death caused by Influenza A in mice.
abstract: Influenza A virus causes annual epidemics which affect millions of people worldwide. A recent Influenza pandemic brought new awareness over the health impact of the disease. It is thought that a severe inflammatory response against the virus contributes to disease severity and death. Therefore, modulating the effects of inflammatory mediators may represent a new therapy against Influenza infection. Platelet activating factor (PAF) receptor (PAFR) deficient mice were used to evaluate the role of the gene in a model of experimental infection with Influenza A/WSN/33 H1N1 or a reassortant Influenza A H3N1 subtype. The following parameters were evaluated: lethality, cell recruitment to the airways, lung pathology, viral titers and cytokine levels in lungs. The PAFR antagonist PCA4248 was also used after the onset of flu symptoms. Absence or antagonism of PAFR caused significant protection against flu-associated lethality and lung injury. Protection was correlated with decreased neutrophil recruitment, lung edema, vascular permeability and injury. There was no increase of viral load and greater recruitment of NK1.1(+) cells. Antibody responses were similar in WT and PAFR-deficient mice and animals were protected from re-infection. Influenza infection induces the enzyme that synthesizes PAF, lyso-PAF acetyltransferase, an effect linked to activation of TLR7/8. Therefore, it is suggested that PAFR is a disease-associated gene and plays an important role in driving neutrophil influx and lung damage after infection of mice with two subtypes of Influenza A. Further studies should investigate whether targeting PAFR may be useful to reduce lung pathology associated with Influenza A virus infection in humans.
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Cristiana C
authors.initials: CC
authors.lastname: Garcia
authors.forename: Remo C
authors.initials: RC
authors.lastname: Russo
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Guabiraba
authors.forename: Caio T
authors.initials: CT
authors.lastname: Fagundes
authors.forename: Rafael B
authors.initials: RB
authors.lastname: Polidoro
authors.forename: Luciana P
authors.initials: LP
authors.lastname: Tavares
authors.forename: Ana Paula C
authors.initials: AP
authors.lastname: Salgado
authors.forename: Geovanni D
authors.initials: GD
authors.lastname: Cassali
authors.forename: Lirlândia P
authors.initials: LP
authors.lastname: Sousa
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Machado
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002645:Chickens; D004095:Dihydropyridines / Q000494:pharmacology; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000472:pathogenicity*; D055370:Lung Injury / Q000378:metabolism* / Q000517:prevention & control / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D010972:Platelet Activating Factor / Q000235:genetics / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D019562:Viral Load
chemical_list: D004095:Dihydropyridines; D018836:Inflammation Mediators; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D051193:Toll-Like Receptors; C039351:platelet activating factor receptor; C066024:PCA 4248