Divergent signaling pathways in phagocytic cells during sepsis.
Neutrophil accumulation in the lung plays a pivotal role in the pathogenesis of acute lung injury during sepsis. Directed movement of neutrophils is mediated by a group of chemoattractants, especially CXC chemokines. Local lung production of CXC chemokines is intensified during experimental sepsis induced by cecal ligation and puncture (CLP), as reflected by rising levels of MIP-2 and cytokine-induced neutrophil chemoattractant-1 in bronchoalveolar lavage fluids. Alveolar macrophages are primed and blood neutrophils are down-regulated for production of MIP-2 and cytokine-induced neutrophil chemoattractant production in response to LPS and C5a. Under these conditions of stimulation, activation of MAPKs (p38, p42/p44) occurs in sham neutrophils but not in CLP neutrophils, while under the same conditions phosphorylation of p38 and p42/p44 occurs in both sham and CLP alveolar macrophages. These data indicate that, under septic conditions, there is impaired signaling in neutrophils and enhanced signaling in alveolar macrophages, resulting in CXC chemokine production, and C5a appears to play a pivotal role in this process. As a result, CXC chemokines increase in lung, setting the stage for neutrophil accumulation in lung during sepsis.
Guo
Ren-Feng
RF
Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109, USA. grf@med.umich.edu
Riedemann
Niels C
NC
Sun
Lei
L
Gao
Hongwei
H
Shi
Kevin X
KX
Reuben
Jayne S
JS
Sarma
Vidya J
VJ
Zetoune
Firas S
FS
Ward
Peter A
PA
D000595:Amino Acid Sequence; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002432:Cecum; D002465:Cell Movement / Q000276:immunology; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011677:Punctures; D051381:Rats; D020318:Rats, Long-Evans; D044087:Receptor, Anaphylatoxin C5a / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*
D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D008070:Lipopolysaccharides; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a