Recombinant tumor necrosis factor increases pulmonary vascular permeability independent of neutrophils.

Abstract

We studied the effects of intravenous infusion of recombinant human tumor necrosis factor type a (rTNF-a;12 pg/kg) on lung fluid balance in sheep prepared with chronic lung lymph fistulas. Recent studies have proposed TNF-a as a mediator of endotoxemia (5) since TNF-a administration mimics the clinical course of endotoxemia (6, 7). Passive immunization against TNF-a reduces the mortality associated with endotoxin challenge (8, 9). Pathologic changes following TNF-a infusion include pulmonary inflammation and hemorrhage, with microaggregates of leukocytes and margination of polymorphonuclear leukocytes (neutrophils; PMNs) in the pulmonary microcirculation (7). Endothelial cells exposed to TNF-a develop cytoskeletal changes (10), procoagulant activity (11,12), and increased adhesiveness to lymphocytes (13) and PMNs (14). TNF-a also causes endothelial cells to release interleukin 1 (15) and platelet-activating factor (16). PMNs stimulated with TNF-a display enhanced adherence (14, 17), migration (18), phagocytic and cytotoxic activities (19), respiratory burst activity (20), and degranulation (20). These effects of TNF-a on endothelial cells and on PMNs suggest that TNF-a is involved in mediating the increase in lung vascular permeability associated with endotoxemia. In the present study, we examined whether recombinant TNF-a (rTNF-a) affected pulmonary vascular permeability by assessing alterations in pulmonary lymph flow in unanesthetized sheep following rTNF-a challenge and by determining transendothelial permeability in rTNF-a-treated endothelial monolayers. We also examined the role of PMNs in the response. MATERIALS AND METHODSChronic lymph fistulas were implanted in male sheep (n = 11) weighing -25 kg (21). This procedure allows collection of blood-free pulmonary lymph after a 3-or 4-day recovery period. Hydroxyurea (HDY; Squibb) was used to deplete circulating neutrophils. HDY (5 g) was dissolved in 200 ml of O.9%o NaCl and the pH was corrected to 7.4; this solution was administered i.v. once daily for 4 or 5 days (200 mg/kg per day). Daily antibiotic treatment was continued in these animals (5 ml i.m.; Ambipen; Butler, Columbus, OH). Animals were studied within 2 days of the last HDY treatment.Awake sheep were studied while standing in a metabolic cage with free access to food and water. A 7.5-F thermodilution catheter (American Edwards Laboratories, Santa Ana, CA) was positioned in the pulmonary artery. Pulmonary artery (Pp) and pulmonary artery wedge (Ppw) pressures were determined with Statham P23Db transducers (Statham, Hato Rey, PR). Pulmonary blood flow (QL) was determined by a thermodilution technique (Cardiac Output Computer, model 9520, American Edwards Laboratories). Pulmonary vascular resistance (PVR) was calculated as (Pp -PPw)/QL. Pulmonary lymph flow (Qlym) (a measure of net pulmonary transvascular fluid filtration rate) was determined by measuring the volume of lymph catheter effluent collected over 15-or 30-min periods. Lymph fluid was collected in plastic tubes containing 100 mg of...

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“…The elevation of TNF-a and IL-1 in ARDS and the role of these cytokines in the production of ARDS have been documented [26,27]. Although ARDS and acute lung injury can occur in neutropenic patients [28] and a neutrophil-depleted animal model [29], several lines of study have suggested that neutrophils play an important role in the production of acute lung injury [1±4]. IL-8 exhibits a chemotactic effect on neutrophils [5].…”

The tissue distribution of tumor necrosis factor biosynthesis during endotoxemia.

“…It is also known that infusion of TNF into animals leads to a pulmonary syndrome similar to human adult respiratory distress syndrome (54,55). However, the production ofTNF by the lung displays compartmentalization; i.e., intravenous endotoxin does not stimulate intrapulmonary TNF secretion in rodents (56) or humans (57), whereas intrapulmonary endotoxin instillation causes pronounced TNF secretion by the lung.…”

Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat.

“…TNF induces the synthesis of endothelial cell surface factors that increase neutrophil adherence to the endothelial surface through mechanism(s) dependent on subunits of the neutrophil membrane adhesion complex CDwl 8 (Mac-I/LFA-I/p1 50,95) (1 1, 22). Horvath et al (23) have shown that intravenous infusion of human TNF into sheep results in increases in pulmonary vascular resistance, transvascular fluid filtration, and transvascular protein clearance. Both in vivo and in vitro studies suggest that TNF increases endothelial permeability to proteins through a neutrophil-independent mechanism (23).…”

“…Horvath et al (23) have shown that intravenous infusion of human TNF into sheep results in increases in pulmonary vascular resistance, transvascular fluid filtration, and transvascular protein clearance. Both in vivo and in vitro studies suggest that TNF increases endothelial permeability to proteins through a neutrophil-independent mechanism (23). TNF has also been reported to trigger platelet-activating factor synthesis by endothelial cells (24).…”