Inflammatory mechanisms underlying the rat pulmonary neutrophil influx induced by airway exposure to staphylococcal enterotoxin type A.
Association between staphylococcal infection and pathogenesis of upper airways disease has been reported. This study aimed to investigate the mechanisms underlying the rat pulmonary inflammation induced by airway exposure to staphylococcal enterotoxin A (SEA). SEA (0.3-10 ng trachea(-1)) caused dose-dependent neutrophil accumulation in BAL fluid, reaching maximal responses at 4 h (25-fold increase for 3 ng trachea(-1)). Significant accumulation of both lymphocytes and macrophages in BAL fluid was also observed at 4 h (2.1- and 1.9-fold increase, respectively, for 3 ng trachea(-1)). At later times (16 h), neutrophil counts in bone marrow (immature forms) and peripheral blood increased by 63 and 81%, respectively. SEA failed to directly induce chemotaxis and adhesion of isolated neutrophils. Analysis of mRNA expression for iNOS, COX-2 and CINC-2 in lung tissue showed an upregulation of these enzymes, which paralleled elevated levels of LTB4, PGE2, TNF-alpha, IL-6 and NO2- in BAL fluid. Expression of CINC-1 was unchanged, whereas CINC-3 was reduced in SEA-treated rats. Incubation of isolated alveolar macrophages with SEA (3 microg ml(-1)) resulted in significant elevations of TNF-alpha and NO2- levels in the cell supernatants. Dexamethasone (0.5 mg kg(-1)), celecoxib (3 mg kg(-1)) and compound 1400 W (5 mg kg(-1)) markedly reduced SEA-induced lung neutrophil influx and NO2- levels in BAL fluid. The lipoxygenase inhibitor AA-861 (100 microg kg(-1)) partly inhibited the neutrophil influx in SEA-treated rats without modifying the NO2- levels. None of these treatments reduced the number of mononuclear cells in BAL fluid (except of dexamethasone, which abolished the increased lymphocyte counts). Our study shows that airways exposure to SEA results in marked neutrophil influx through mechanisms involving increased expressions of CINC-2, iNOS and COX-2, as well as enhanced production of NO, PGE2, LTB4, TNF-alpha and IL-6.
Desouza
Ivani A
IA
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), PO Box 6111, 13084-971, Campinas (SP), Brazil. ivanidesouza@uol.com.br
Franco-Penteado
Carla F
CF
Camargo
Enilton A
EA
Lima
Carmen S P
CS
Teixeira
Simone A
SA
Muscará
Marcelo N
MN
De Nucci
Gilberto
G
Antunes
Edson
E
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics; D015232:Dinoprostone / Q000032:analysis; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007378:Interleukins / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000166:cytology; D007975:Leukotriene B4 / Q000032:analysis; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000276:immunology / Q000494:pharmacology; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009573:Nitrites / Q000032:analysis; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; C513294:Cxcl3 protein, rat; D004768:Enterotoxins; D036341:Intercellular Signaling Peptides and Proteins; D007378:Interleukins; D009573:Nitrites; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; C026066:enterotoxin A, Staphylococcal; D009240:N-Formylmethionine Leucyl-Phenylalanine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone