Potential role of IL-8, platelet-activating factor and TNF-alpha in the sequestration of neutrophils in the lung: effects on neutrophil deformability, adhesion receptor expression, and chemotaxis.
The microvasculature of the normal lung contains a pool of sequestered neutrophils, which is markedly enhanced in acute lung inflammation. Lung neutrophil sequestration is determined by the cells' deformability and adhesivity to capillary endothelium, and is a pre-requisite for emigration into the airspaces. We assessed the effect of several pro-inflammatory mediators associated with acute lung inflammation on these factors. Platelet-activating factor, IL-8 and formyl-Met-Leu-Phe (fMLP) induced a marked, but transient reduction in neutrophil deformability. Also, increased surface expression of the beta(2)-integrin and CD11b, and shedding of L-selectin (CD62L) was observed for these stimuli. TNF-alpha in contrast caused a small decrease in cell deformability only after 30 min, and shedding of L-selectin, but no change in CD11b levels. However, TNF-alpha-pretreatment markedly enhanced the fMLP response for cell deformability, CD11b expression and CD62L loss. Moreover, all pre-treatments were found to induce chemokinesis, and all except fMLP, enhanced fMLP-directed chemotaxis. We were able to demonstrate, using specific TNF-alpha receptor antagonists, that the TNF-alpha-induced changes in chemotaxis were mediated through the 55-kDa receptor. Also, inhibitors of the mitogen activated protein (MAP) kinase signaling pathway showed that the p38 MAP kinase pathway was involved for fMLP-directed chemotaxis of TNF-pretreated neutrophils, although activation of the extracellular signal-regulated kinase (ERK) pathway was also seen. These data demonstrate the differential role of pro-inflammatory mediators in controlling neutrophil sequestration and migration, which may orchestrate the severity of the inflammatory response in such respiratory diseases as chronic obstructive pulmonary disease and asthma.
Drost
Ellen M
EM
Edinburgh Lung and Environmental Group Initiative (ELEGI)/Colt Laboratories, Department of Medical and Radiological Sciences, Wilkie Building, The Medical School, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland, UK.
MacNee
William
W
D002448:Cell Adhesion; D002465:Cell Movement; D048429:Cell Size; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000494:pharmacology / Q000502:physiology; D016209:Interleukin-8 / Q000494:pharmacology / Q000502:physiology*; D019041:L-Selectin / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D010972:Platelet Activating Factor / Q000494:pharmacology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D018836:Inflammation Mediators; D016209:Interleukin-8; D016177:Macrophage-1 Antigen; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D020928:Mitogen-Activated Protein Kinases