Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep

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Abstract
The macrophage- and monocyte-produced cytokine tumor necrosis factor alpha (TNF.alpha.) has been proposed as a major mediator of endotoxin-induced injury. To determine if TNF.alpha. could reproduce the effects of endotoxin on the lung, we intravenously administered 10 .mu.g/kg of human recombinant TNF.alpha. into five chronically instrumented unanesthetized sheep on two occasions to characterize the TNF.alpha. response and its reproducibility. We assessed changes in lung mechanics, pulmonary and systemic hemodynamics, gas exchange, and the number and type of peripheral blood leukocytes. We also determined airway reactivity by use of aerosolized histamine before and after TNF.alpha. infusion. Pulmonary arterial pressure (Ppa) peaked within 30 min of initiating the TNF.alpha. infusion [47.7 .+-. 2.2 vs. 15.9 .+-. 0.4 (SE) cmH2O at base line] and then returned toward base line over 4 h. There was a brief decline in left atrial pressure after TNF.alpha.. Pulmonary hypertension was accompanied by leukopenia, neutropenia, and increases in the alveolar-arterial O2 difference (AaDo2). Dynamic lung compliance (Cdyn) declined after TNF.alpha., reaching a nadir within 15 min of the initiation of the TNF.alpha. infusion [0.045 .+-. 0.007 vs 0.093 .+-. 0.007 (.+-.SE) l/cmH2O at base line]. Resistance to airflow across the lung (RL) increased from 1.2 .+-. 0.2 cmH2O .cntdot. l-1 at base line, peaking at 5.4 .+-. 1.3 cmH2O .cntdot. l-1 .cntdot. s 30 min after the start of the TNF.alpha. infusion. Alterations in Cdyn and RL persisted for 4 h. Lung mechanics were measured and airway reactivity was tested in nine additional sheep by use of incremental aerosolized histamine inhalation before and 6 h after TNF.alpha. administration. The concentration of histamine required to reduce Cdyn to 65% of base line declined by approximately one log dose from 8.4 .+-. 1.7 to 0.4 .+-. 0.3 mg/ml. Cdyn and RL did not differ at any time point between sheep undergoing histamine airway reactivity testing before TNF.alpha. infusion and the five animals receiving TNF.alpha. alone. We conclude that TNF.alpha. causes acute physiological changes in awake sheep and alterations in airway reactivity qualitatively similar to those of endotoxin. Because TNF.alpha. is known to be produced after endotoxin stimulation, TNF.alpha. may in part mediate the changes in the lung seen after endotoxemia.