Alterations in Gene Expressions Encoding PreproET-1 and NOS in Pulmonary Tissue in Endotoxemic Rats

Abstract

Septic shock is characterized by hypotension and a hyporeactive response to vasopressor agents. The pathogenesis is due to vascular leaks and an increased synthesis of cytokines and nitric oxide (NO). The present study examined the time-dependent alterations of endothelin-1 (ET-1) and the expression of NO synthase (NOS) in lung tissue in a septic rat model. Normal Sprague-Dawley (SD) rats aged 10 weeks received 15 mg/kg lipopolysaccharide (LPS) and then were sacrificed at different time points (1, 3, 6, and 10 hrs). Rats that did not receive LPS were considered to be controls. Both systolic and diastolic pressure decreased in SD rats after LPS administration. Time-dependent onset of features of acute lung injury, such as the infiltration of inflammatory cells and thickening of alveolar septa, were seen in rats that received LPS. A 2.8-fold increase in the expression of preproET-1 level was observed in lung tissue 6 hrs after LPS administration. The expression of endothelial NOS (eNOS) was also altered in lung tissue in a time-dependent fashion. After the administration of LPS, there was a 16-fold increase in the expression of eNOS mRNA. The peak expression of inducible NOS (iNOS) in lung tissue specimens obtained from rats that received LPS was 45-fold higher than that in control rats. ET-1 is a potent vasoconstrictor and thereby may play an important role in the pathogenesis of acute lung injury in a septic rat model. The increased expression of NOS may result in excess NO production and may also play a role in the pulmonary complications of endotoxemia.

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References

Root RK, Jacobs R. Septicemia and septic shock. In: Wilson JD, Braunwald E, Isselbacher JK, Eds. Harrison’s Principles of Internal Medicine (12th ed.). New York: McGraw-Hill, pp502–507, 1991.

Wright CE, Rees DD, Moncada S. Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 26:48–57, 1992.

Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471–1477, 1993.

Szabo C, Mitchell JA, Thiemermann C, Vane JR. Nitric oxide–mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol 108:786–792, 1993.

Brigham KL, Meyrick B. Endotoxin and lung injury. Am Rev Respir Dis 133:913–927, 1986.

Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415, 1988.

Mitaka C, Hirata Y, Nagura T, Tsunoda Y, Amaha K. Circulating endothelin-1 concentrations in acute respiratory failure. Chest 104:476–480, 1993.

Battistini B, Forget MA, Laight D. Potential roles for endothelins in systemic inflammatory response syndrome with a particular relation to cytokines. Shock 5:167–183, 1996.

Pernow J, Hemsen A, Lundberg JM. Increased plasma levels of endothelin-like immunoreactivity during endotoxin administration in the pig. Acta Physiol Scand 137:317–318, 1989.

10.

Nakamura T, Kasai K, Sekiguchi Y, Banba N, Takahashi K, Emoto T, Hattori Y, Shimoda S. Elevation of plasma endothelin concentrations during endotoxin shock in dogs. Eur J Pharmacol 205:277–282, 1991.

11.

Pittet J, Morel D, Hemsen A, Gunning K, Lacroix JS, Suter P, Lundberg J. Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsis. Ann Surg 213:261–264, 1991.

12.

Weitzberg E, Lundberg JM, Rudehill A. Elevated plasma levels of endothelin in patients with sepsis syndrome. Circ Shock 33:222–227, 1991.

13.

Henry PJ, Rigby PJ, Self GJ, Preuss JM, Goldie RG. Relationship between endothelin-1 binding site densities and constrictor activities in human and animal airway smooth muscle. Br J Pharmacol 100:786–792, 1990.

14.

McKay KO, Black JL, Diment LM, Armour CL. Functional and autoradiographic studies of endothelin-1 and endothelin-2 in human bronchi, pulmonary arteries, and airway parasympathetic ganglia. J Cardiovasc Pharmacol 17:S206–209, 1991.

15.

Horgan MJ, Pinheiro JM, Malik AB. Mechanism of endothelin-1–induced pulmonary vasoconstriction. Circ Res 69:157–164, 1991.

16.

Filep JG, Sirois MG, Rousseau A, Fournier A, Sirois P. Effects of endothelin-1 on vascular permeability in the conscious rat: interactions with platelet-activating factor. Br J Pharmacol 104:797–804, 1991.

17.

Helset E, Kjaeve J, Hauge A. Endothelin-1–induced increases in microvascular permeability in isolated, perfused rat lungs requires leukocytes and plasma. Circ Shock 39:15–20, 1993.

18.

Takahashi K, Silva A, Cohen J, Lam HC, Ghatei MA, Bloom SR. Endothelin immunoreactivity in mice with gram-negative bacteraemia: relationship to tumor necrosis factor–alpha. Clin Sci 79:619–623, 1990.

19.

Ruetten H, Thiemermann C, Vane JR. Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxemic shock in the anesthetized rat. Br J Pharmacol 118:198–204, 1996.

20.

Bigatello L, Zapol WM. New approaches to acute lung injury. Br J Anaesth 77:99–109, 1996.

21.

Krafft P, Fridrich P, Pernerstofer T, Fitzgerald RD, Koc D, Schneider B, Hammerle AF, Steltzer H. The acute respiratory distress syndrome: definitions, severity and clinical outcome: an analysis of 101 clinical investigations. Int Care Med 22:519–529, 1996.

22.

Druml W, Steltzer H, Waldhausl W, Lenz K, Hammerle A, Vierhapper H, Gasic S, Wagner OF. Endothelin-1 in adult respiratory distress syndrome. Am Rev Respir Dis 148:1169–1173, 1993.

23.

Langleben D, DeMarchie M, Laporta D, Spanier AH, Schlesinger RD, Stewart DJ. Endothelin-1 in acute lung injury and the adult respiratory distress syndrome. Am Rev Respir Dis 148:1646–1650, 1993.

24.

Michael JR, Markewitz BA. Endothelins and the lung. Am J Respir Crit Care Med 154:555–581, 1996.

25.

Shindo T, Kurihara H, Kurihara Y, Morita H, Yazaki Y. Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model. J Cardiovasc Pharmacol 31:S541–544, 1998.

26.

Ishizaki T, Shigemori K, Nakai T, Miyabo S, Hayakawa M, Ozawa T, Voelkel NF, Chang SW. Endothelin-1 potentiates leukotoxin-induced edematous lung injury. J Appl Physiol 79:1106–1111, 1995.

27.

Langleben D, DeMarchie M, Laporta D, Spanier AH, Schlesinger RD, Stewart DJ. Endothelin-1 in acute lung injury and the adult respiratory distress syndrome. Am Rev Respir Dis 148:1646–1650, 1993.

28.

Akaike T, Noguchi Y, Ijiri S, Setoguchi S, Suga M, Zheng YM, Dietzschold B, Maeda H. Pathogenesis of influenza virus–induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proc Natl Acad Sci U S A 93:2448–2453, 1996.

29.

Hortelano S, Genaro AM, Bosca L. Phorbol esters induce nitric oxide synthase and increase arginine influx in cultured peritoneal macrophages. FEBS Lett 320:135–139, 1993.

30.

Moncada S, Higgs A. The l-arginine–nitric oxide pathway. N Engl J Med 329:2002–2012, 1993.

31.

Yamashita T, Kawashima S, Ohashi Y, Ozaki M, Ueyama T, Ishida T, Inoue N, Hirata K, Akita H, Yokoyama M. Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation 101:931–937, 2000.

32.

Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Laubach VE, Sherman PA, Sessa WC, Smithies O. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 93:13,176–13,181, 1996.