title: Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence.
abstract: Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents that attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.
authors.affiliation: Department of Medicine, Stanford University Medical Center, California 94305-5236.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: J J
authors.initials: JJ
authors.lastname: Crowley
authors.forename: J C
authors.initials: JC
authors.lastname: Chan
authors.forename: H
authors.initials: H
authors.lastname: Hoffmann
authors.forename: J R
authors.initials: JR
authors.lastname: Hatherill
authors.forename: A
authors.initials: A
authors.lastname: Ishizaka
authors.forename: T A
authors.initials: TA
authors.lastname: Raffin
mesh_terms: D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002417:Cattle; D002470:Cell Survival; D002478:Cells, Cultured; D002860:Chromium Radioisotopes; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D010431:Pentoxifylline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
chemical_list: D002860:Chromium Radioisotopes; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D000628:Aminophylline; D002110:Caffeine; D003994:Bucladesine; D010431:Pentoxifylline