Tumor necrosis factor causes bronchial hyperresponsiveness in rats.

We have previously reported that exposure of rats to aerosolized endotoxin (LPS) causes a transient, dose-dependent increase in bronchial responsiveness (BR) to 5 hydroxytryptamine (5HT), 90 min after exposure. In the present study we examined whether LPS induces the release of tumor necrosis factor (TNF) in the airways and whether TNF contributes to the increase in BR. After 90 min following exposure to aerosolized LPS, at a concentration of 1 or 10 micrograms/ml, TNF concentrations in bronchoalveolar lavage (BAL) fluid were 17.9 +/- 6.9 and 80.5 +/- 7.8 U/ml, respectively. No TNF was detected in BAL fluid of saline-exposed animals. At 90 min after exposure to aerosolized recombinant human TNF (rhTNF) (1 microgram/ml) an increase in BR was observed: the provocative concentration of 5HT causing a 50% increase in lung resistance (PC50RL 5HT) was 2.7 +/- 0.4 versus 4.4 +/- 0.3 microgram/kg in saline-exposed animals (p less than 0.01). Pretreatment with anti-TNF antibodies 30 min before LPS exposure significantly diminished the increase in BR: PC50RL 5HT was 2.3 +/- 0.4 versus 1.2 +/- 0.5 microgram/kg in control pretreated LPS-exposed rats (p less than 0.01). Exposure to aerosolized TNF also induced a significant influx of neutrophils in BAL fluid (12.1 +/- 3.7 versus 1.7 +/- 0.4% in saline-exposed animals) (p less than 0.01). The LPS-induced neutrophil influx in BAL fluid was partly inhibited by pretreatment with anti-TNF antibodies (55.2 +/- 5.1 versus 76.0 +/- 3.9%) (p less than 0.01). We conclude that TNF causes bronchial hyperresponsiveness and airway inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

[1]  A. B. Kay,et al.  Asthma and inflammation. , 1991, The Journal of allergy and clinical immunology.

[2]  R. Pauwels,et al.  The effect of endotoxin inhalation on airway responsiveness and cellular influx in rats. , 1990, The American review of respiratory disease.

[3]  B. Beutler,et al.  The biology of cachectin/TNF--a primary mediator of the host response. , 1989, Annual review of immunology.

[4]  B. Beutler,et al.  Tumor necrosis factor α stimulates leukotriene production in vivo , 1988 .

[5]  D. Liggitt,et al.  Lung-specific delivery of cytokines induces sustained pulmonary and systemic immunomodulation in rats. , 1988, Journal of immunology.

[6]  Kevin J. Tracey,et al.  Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia , 1987, Nature.

[7]  W. Fiers,et al.  The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[8]  N. Voelkel,et al.  Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats. , 1987, The Journal of clinical investigation.

[9]  A. Mantovani,et al.  Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. , 1987, Journal of immunology.

[10]  J. D. Albert,et al.  Shock and tissue injury induced by recombinant human cachectin. , 1986, Science.

[11]  J. Gamble,et al.  Stimulation of neutrophils by tumor necrosis factor. , 1986, Journal of immunology.

[12]  J. Larrick,et al.  Tumor necrosis factor stimulates interleukin-1 and prostaglandin E2 production in resting macrophages. , 1986, Biochemical and biophysical research communications.

[13]  J. Gamble,et al.  Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[14]  B. Beutler,et al.  Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. , 1985, Science.

[15]  R. Rylander,et al.  Airborne endotoxins and humidifier disease , 1984, Clinical allergy.

[16]  J. Snapper,et al.  Effect of endotoxin on airway responsiveness to aerosol histamine in sheep. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[17]  M. Chan-yeung,et al.  Clinical features and natural history of occupational asthma due to western red cedar (Thuja plicata). , 1982, The American journal of medicine.

[18]  P. Halushka,et al.  Elevated thromboxane levels in the rat during endotoxic shock: protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency. , 1980, The Journal of clinical investigation.

[19]  S. Bradley.  Cellular and molecular mechanisms of action of bacterial endotoxins. , 1979, Annual review of microbiology.

[20]  H. D. Hochstein,et al.  Allergenic and biologic activity of commercial preparations of house dust extract. , 1978, The Journal of allergy and clinical immunology.

[21]  B. Mehlman,et al.  Early Histamine Release and Death Due to Endotoxin , 1971, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.