Delay of LPS-induced acute lung injury resolution by soluble immune complexes is neutrophil dependent.
The pathophysiological role of soluble immune complexes (SICXs) and its relationship with neutrophils were investigated in LPS-induced acute lung injury (ALI) animal model (Sprague-Dawley rat) and through the in vitro studies. Results showed that LPS-induced SICX was timely related to changes of tumor necrosis factor alpha and macrophage inflammatory protein 2 (inflammatory cytokines) in bronchoalveolar lavage fluid. In vitro study showed that SICX can bind to Fc gammaR (CD64 and CD32 or CD16) to prevent the apoptosis of neutrophils. The SICX-mediated apoptosis inhibition was extracellular signal-regulated kinase (ERK) or phosphoinositide 3 kinase dependent and was interrupted by PD98059 and LY294002. In vivo, additional amount of SICX exacerbated the lung injury caused by LPS. LPS-induced lung injury and macrophage inflammatory protein 2 release, however, were prevented by CD64 and CD32 blockers (decoy antibodies). In conclusion, excessive amount of SICX in lung can act through Fc gammaRs to protect bronchoalveolar lavage fluid neutrophils from apoptosis that eventually lead to delayed resolution of ALI caused by LPS. Blockade of SICX engagement of CD32 and CD64 (with decoy antibodies) could interrupt SICX-mediated protection of neutrophils and protect lung from LPS-induced injury. The decoy antibodies may therefore have therapeutic utility in ALI.
Wu
Chieh-Liang
CL
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
Lin
Liang-Yi
LY
Yeh
Hsueh-Mei
HM
Chan
Ming-Cheng
MC
Yang
Chih-Hsueh
CH
Hsueh
Chi-Mei
CM
D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054426:Chemokine CXCL2 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017452:Receptors, IgG / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000936:Antigen-Antibody Complex; D054426:Chemokine CXCL2; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008070:Lipopolysaccharides; D009025:Morpholines; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one