title: The role of cyclooxygenase products in lung injury induced by tumor necrosis factor in sheep.
abstract: Tumor necrosis factor-alpha (TNF alpha) has been proposed as a mediator of endotoxin-induced lung injury. When given to sheep, TNF alpha mimics endotoxin (LPS) causing hypoxemia, pulmonary hypertension, leukopenia, reduced dynamic compliance (Cdyn), increased resistance to airflow (RL), exudation of lung lymph, and enhanced airway reactivity. TNF alpha also induces rapid release of thromboxane A2 (TxA2), prostaglandin E2 (PGE2), and prostacyclin (PGI2). We hypothesized that the inflammatory effects of TNF alpha are due at least in part to cyclooxygenase products, and therefore cyclooxygenase inhibition would have similar effects on TNF alpha-induced lung injury as has previously been demonstrated for LPS-induced lung damage. Using awake sheep with chronic lung lymph fistulas, we measured Cdyn, RL, and FRC using a whole-body plethysmograph. Pulmonary artery (Ppa), left atrial (PLA), and systemic arterial (Psa) pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples (for prostanoid levels) were collected every 30 min. Eleven animals underwent paired random-order experiments receiving ibuprofen (14 mg/kg) 1 h before human recombinant TNF alpha (10 micrograms/kg), or an identical dose of TNF alpha alone. Within 15 min of initiating TNF alpha, Ppa doubled and remained elevated for 4 h. Ibuprofen prevented the early rise in Ppa after TNF alpha. In the group receiving TNF alpha alone, increases in Ppa were accompanied by a 60% decline in leukocyte count and a 50% increase in AaPo2 within 30 min. Ibuprofen prevented increases in AaPo2, but it had no effect on leukopenia or late increases in lymph flow.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN 37232.
authors.forename: A P
authors.initials: AP
authors.lastname: Wheeler
authors.forename: W D
authors.initials: WD
authors.lastname: Hardie
authors.forename: G R
authors.initials: GR
authors.lastname: Bernard
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000032:analysis; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007052:Ibuprofen / Q000627:therapeutic use; D008171:Lung Diseases / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D008196:Lymph / Q000737:chemistry / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011994:Recombinant Proteins / Q000633:toxicity; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D015777:Eicosanoids; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen