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S-nitroso human serum albumin given after LPS challenge reduces acute lung injury and prolongs survival in a rat model of endotoxemia

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Abstract

Endotoxemia leads to the induction of inducible nitric oxide synthase (NOS-2) and increased expression of numerous inflammatory mediators contributing to endotoxin-induced acute lung injury. We tested the hypothesis that supplementation of nitric oxide (NO) by the novel NO donor S-nitroso human serum albumin (S-NO-HSA) given after lipopolysaccharide (LPS) challenge may reduce NOS-2 expression, lung inflammation and acute lung injury. Rats were divided into four groups: sham-operated (no treatment), LPS, LPS+HSA (human serum albumin), and LPS+S-NO-HSA. LPS was administered intravenously (20 mg kg−1) resulting in acute lung injury and a high mortality rate within 6 h (>90%). LPS-induced lung injury was characterized by an increased lung edema (lung wet/dry weight ratio), pulmonary neutrophil infiltration (myeloperoxidase activity, MPO) as well as a robust inflammatory response [increased expression of intercellular adhesion molecule-1 (ICAM-1), NOS-2, and cyclooxygenase-2 (COX-2)]. Infusion of S-NO-HSA or HSA was started 2 h after LPS and continued for 4 h (total dose of 72 mg kg−1) at a rate of 300 μg kg−1 min−1. S-NO-HSA but not HSA prolonged survival of endotoxemic rats, reduced the hypotensive response to LPS, minimized LPS-induced lung edema and injury, normalized MPO activity as well as diminished lung expression of pro-inflammatory molecules such as ICAM-1, NOS-2, and COX-2. Continuous supplementation of NO by S-NO-HSA after LPS challenge prevents induction of NOS-2, provides significant protection of endotoxin-induced acute lung injury, and prevents early mortality in endotoxic shock in rats. Our results suggest a potential therapeutic role for S-NO-HSA in endotoxemia.

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Abbreviations

ARDS:

acute respiratory distress syndrome

HSA:

human serum albumin

LPS:

lipopolysaccharide

MAP:

mean arterial blood pressure

MPO:

myeloperoxidase

S-NO-GSH:

S-nitroso-glutathione

S-NO-HSA:

S-nitroso human serum albumin

SNAP:

S-nitroso-N-acetyl-penicyllamine

References

  • Anderson FL, Jubiz W, Tsagaris TJ, Kuida H (1975) Endotoxin-induced prostaglandin E and F release in dogs. Am J Physiol 228:410–414

    PubMed  CAS  Google Scholar 

  • Bauer JA, Fung HL (1991) Differential hemodynamic effects and tolerance properties of nitroglycerin and an S-nitrosothiol in experimental heart failure. J Pharmacol Exp Ther 256:249–254

    PubMed  CAS  Google Scholar 

  • Bauer C, Kuntz W, Ohnsmann F, Gasser H, Weber C, Redl H, Marzi I (2004) The attenuation of hepatic microcirculatory alterations by exogenous substitution of nitric oxide by S-nitroso-human albumin after hemorrhagic shock in the rat. Shock 21:165–169

    Article  PubMed  CAS  Google Scholar 

  • Biffl WL, Moore EE, Moore FA, Barnett C (1996) Nitric oxide reduces endothelial expression of intercellular adhesion molecule (ICAM)-1. J Surg Res 63:328–332

    Article  PubMed  CAS  Google Scholar 

  • Chlopicki S, Bartus JB, Walski M, Wolkow PP, Gryglewski RJ (2001) Nitric oxide—a safequard of pulmonary microcirculation in early endotoxaemia. In: Gryglewski RJ, Minuz P (eds) Nitric oxide. Basic research and clinical applications. IOS, Amsterdam, pp 137–148

    Google Scholar 

  • Chlopicki S, Walski M, Bartus JB (2005) Ultrastructure of immediate microvascular lung injury induced by bacterial endotoxin in the isolated, no-deficient lung perfused with full blood. J Physiol Pharmacol 56(Suppl 4):47–64

    PubMed  Google Scholar 

  • Cifuentes J, Ruiz-Oronoz J, Myles C, Nieves B, Carlo WA, Matalon S (1995) Interaction of surfactant mixtures with reactive oxygen and nitrogen species. J Appl Physiol 78:1800–1805

    PubMed  CAS  Google Scholar 

  • Clancy RM, Leszczynska-Piziak J, Abramson SB (1992) Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J Clin Invest 90:1116–1121

    Article  PubMed  CAS  Google Scholar 

  • Cobb JP (1999) Use of nitric oxide synthase inhibitors to treat septic shock: the light has changed from yellow to red [editorial; comment]. Crit Care Med 27:855–856

    Article  PubMed  CAS  Google Scholar 

  • Davenpeck KL, Gauthier TW, Lefer AM (1994) Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation. Gastroenterology 107:1050–1058

    PubMed  CAS  Google Scholar 

  • Doerschuk CM, Mizgerd JP, Kubo H, Qin L, Kumasaka T (1999) Adhesion molecules and cellular biomechanical changes in acute lung injury: Giles F. Filley lecture. Chest 116:S37–S43

    Article  Google Scholar 

  • Feelisch M (1991) The biochemical pathways of nitric oxide formation from notrosovasodilators: appropriate choice of exogenous NO donors and aspects of preparation and handling of aqueous solutions. J Cardiovasc Pharmacol 17:S25–S33

    Article  CAS  Google Scholar 

  • Gluckman TL, Grossman JE, Folts JD, Kruse-Elliott KT (2000) Regulation of leukocyte function by nitric oxide donors: the effect of S-nitroso-thiol complexes. J Toxicol Environ Health A 61:9–26

    Article  PubMed  CAS  Google Scholar 

  • Gluckman TL, Grossman JE, Folts JD, Kruse-Elliott KT (2002) Modulation of endotoxin-induced cardiopulmonary dysfunction by S-nitroso-albumin. J Endotoxin Res 8:17–26

    PubMed  CAS  Google Scholar 

  • Griscavage JM, Hobbs AJ, Ignarro LJ (1995) Negative modulation of nitric oxide synthase by nitric oxide and nitroso compounds. Adv Pharmacol 34:215–234

    Article  PubMed  CAS  Google Scholar 

  • Gryglewski RJ, Wolkow PP, Uracz W, Janowska E, Bartus JB, Balbatun O, Patton S, Brovkovych V, Malinski T (1998) Protective role of pulmonary nitric oxide in the acute phase of endotoxemia in rats. Circ Res 82:819–827

    PubMed  CAS  Google Scholar 

  • Guidot DM, Hybertson BM, Kitlowski RP, Repine JE (1996) Inhaled NO prevents IL-1-induced neutrophil accumulation and associated acute edema in isolated rat lungs. Am J Physiol 271:L225–L229

    PubMed  CAS  Google Scholar 

  • Hallström S, Gasser H, Neumayer C, Fugl A, Nanobashvili J, Jakubowski A, Huk I, Schlag G, Malinski T (2002) S-nitroso human serum albumin treatment reduces ischemia/reperfusion injury in skeletal muscle via nitric oxide release. Circulation 105:3032–3038

    Article  PubMed  CAS  Google Scholar 

  • Hallström S, Franz M, Gasser H, Vodrazka M, Semsroth S, Losert UM, Haisjackl M, Podesser BK, Malinski T (2008) S-nitroso human serum albumin reduces ischaemia/reperfusion injury in the pig heart after unprotected warm ischaemia. Cardiovasc Res 77:506–514

    Article  PubMed  CAS  Google Scholar 

  • Harbrecht BG, Billiar TR, Stadler J, Demetris AJ, Ochoa JB, Curran RD, Simmons RL (1992) Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia. Crit Care Med 20:1568–1574

    Article  PubMed  CAS  Google Scholar 

  • Huk I, Nanobashvili J, Neumayer C, Punz A, Mueller M, Afkhampour K, Mittlboeck M, Losert U, Polterauer P, Roth E, Patton S, Malinski T (1997) l-arginine treatment alters the kinetics of nitric oxide and superoxide release and reduces ischemia/reperfusion injury in skeletal muscle. Circulation 96:667–675

    PubMed  CAS  Google Scholar 

  • Katsuyama K, Shichiri M, Marumo F, Hirata Y (1998) NO inhibits cytokine-induced iNOS expression and NF-kappaB activation by interfering with phosphorylation and degradation of IkappaB-alpha. Arterioscler Thromb Vasc Biol 18:1796–1802

    PubMed  CAS  Google Scholar 

  • Kessler E, Hughes RC, Bennett EN, Nadela SM (1973) Evidence for the presence of prostaglandin-like material in the plasma of dogs with endotoxin shock. J Lab Clin Med 81:85–94

    PubMed  CAS  Google Scholar 

  • Kirkeboen KA, Strand OA (1999) The role of nitric oxide in sepsis—an overview. Acta Anaesthesiol Scand 43:275–288

    Article  PubMed  CAS  Google Scholar 

  • Kubes P, Suzuki M, Granger DN (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 88:4651–4655

    Article  PubMed  CAS  Google Scholar 

  • Laszlo F, Whittle BJ, Moncada S (1994) Time-dependent enhancement or inhibition of endotoxin-induced vascular injury in rat intestine by nitric oxide synthase inhibitors. Br J Pharmacol 111:1309–1315

    PubMed  CAS  Google Scholar 

  • Laszlo F, Whittle BJ, Moncada S (1995) Attenuation by nitrosothiol NO donors of acute intestinal microvascular dysfunction in the rat. Br J Pharmacol 115:498–502

    PubMed  CAS  Google Scholar 

  • Lipsky PE (1999) Specific COX-2 inhibitors in arthritis, oncology, and beyond: where is the science headed? J Rheumatol Suppl 56:25–30

    PubMed  CAS  Google Scholar 

  • Meziani F, Kremer H, Tesse A, Baron-Menguy C, Mathien C, Mostefai HA, Carusio N, Schneider F, Asfar P, Andriantsitohaina R (2007) Human serum albumin improves arterial dysfunction during early resuscitation in mouse endotoxic model via reduced oxidative and nitrosative stresses. Am J Pathol 171:1753–1761

    Article  PubMed  CAS  Google Scholar 

  • Michael JR, Barton RG, Saffle JR, Mone M, Markewitz BA, Hillier K, Elstad MR, Campbell EJ, Troyer BE, Whatley RE, Liou TG, Samuelson WM, Carveth HJ, Hinson DM, Morris SE, Davis BL, Day RW (1998) Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS. Am J Respir Crit Care Med 157:1372–1380

    PubMed  CAS  Google Scholar 

  • Munzel T, Daiber A, Ullrich V, Mulsch A (2005) Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol 25:1551–1557

    Article  PubMed  CAS  Google Scholar 

  • Nava E, Palmer RM, Moncada S (1991) Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? Lancet 338:1555–1557

    Article  PubMed  CAS  Google Scholar 

  • Neviere R, Guery B, Mordon S, Zerimech F, Charre S, Wattel F, Chopin C (2000) Inhaled NO reduces leukocyte-endothelial cell interactions and myocardial dysfunction in endotoxemic rats. Am J Physiol Heart Circ Physiol 278:H1783–H1790

    PubMed  CAS  Google Scholar 

  • Offner PJ, Robertson FM, Pruitt BA Jr (1995) Effects of nitric oxide synthase inhibition on regional blood flow in a porcine model of endotoxic shock. J Trauma 39:338–343

    Article  PubMed  CAS  Google Scholar 

  • Olszanecki R, Chlopicki S (1999) Endotoxaemia in rats: role of NO, PAF and TXA2 in pulmonary neutrophil sequestration and hyperlactataemia. J Physiol Pharmacol 50:443–454

    PubMed  CAS  Google Scholar 

  • Olszanecki R, Kozlovski VI, Chlopicki S, Gryglewski RJ (2002) Paradoxical augmentation of bradykinin-induced vasodilatation by xanthine/xanthine oxidase-derived free radicals in isolated guinea pig heart. J Physiol Pharmacol 53:689–699

    PubMed  CAS  Google Scholar 

  • Park JH, Chang SH, Lee KM, Shin SH (1996) Protective effect of nitric oxide in an endotoxin-induced septic shock. Am J Surg 171:340–345

    Article  PubMed  CAS  Google Scholar 

  • Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM (1992) Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 267:24173–24176

    PubMed  CAS  Google Scholar 

  • Razavi HM, Werhun R, Scott JA, Weicker S, Wang LF, McCormack DG, Mehta S (2002) Effects of inhaled nitric oxide in a mouse model of sepsis-induced acute lung injury. Crit Care Med 30:868–873

    Article  PubMed  CAS  Google Scholar 

  • Sato Y, Walley KR, Klut ME, English D, D’yachkova Y, Hogg JC, van Eeden SF (1999) Nitric oxide reduces the sequestration of polymorphonuclear leukocytes in lung by changing deformability and CD18 expression. Am J Respir Crit Care Med 159:1469–1476

    PubMed  CAS  Google Scholar 

  • Sato E, Simpson KL, Grisham MB, Koyama S, Robbins RA (2000) Inhibition of MIP-1alpha-induced human neutrophil and monocyte chemotactic activity by reactive oxygen and nitrogen metabolites. J Lab Clin Med 135:161–169

    Article  PubMed  CAS  Google Scholar 

  • Semsroth S, Fellner B, Trescher K, Bernecker OY, Kalinowski L, Gasser H, Hallström S, Malinski T, Podesser BK (2005) S-nitroso human serum albumin attenuates ischemia/reperfusion injury after cardioplegic arrest in isolated rabbit hearts. J Heart Lung Transplant 24:2226–2234

    Article  PubMed  Google Scholar 

  • Shoup M, He LK, Liu H, Shankar R, Gamelli R (1998) Cyclooxygenase-2 inhibitor NS-398 improves survival and restores leukocyte counts in burn infection. J Trauma 45:215–220

    Article  PubMed  CAS  Google Scholar 

  • Shultz PJ, Raij L (1992) Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J Clin Invest 90:1718–1725

    Article  PubMed  CAS  Google Scholar 

  • Spain DA, Wilson MA, Garrison RN (1994) Nitric oxide synthase inhibition exacerbates sepsis-induced renal hypoperfusion. Surgery 116:322–330

    PubMed  CAS  Google Scholar 

  • Thiemermann C (1997) Nitric oxide and septic shock. Gen Pharmacol 29:159–166

    PubMed  CAS  Google Scholar 

  • Uhlig S (1998) The isolated perfused lung. In: Uhlig S, Taylor AE (eds) Methods in pulmonary research. Birkhauser Verlag, Basel

    Google Scholar 

  • Walley KR, McDonald TE, Wang Y, Dai S, Russell JA (2003) Albumin resuscitation increases cardiomyocyte contractility and decreases nitric oxide synthase II expression in rat endotoxemia. Crit Care Med 1:187–194

    Article  Google Scholar 

  • Weinberger B, Fakhrzadeh L, Heck DE, Laskin JD, Gardner CR, Laskin DL (1998) Inhaled nitric oxide primes lung macrophages to produce reactive oxygen and nitrogen intermediates. Am J Respir Crit Care Med 158:931–938

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Austro-Polish exchange programs (MZ/1/L/2005 and MZ/1/L/2006) and by the Polish Ministry of Science and Higher Education (grant No. N N401015135).

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Correspondence to S. Hallström or S. Chlopicki.

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A. Jakubowski and N. Maksimovich contributed equally to this work.

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Jakubowski, A., Maksimovich, N., Olszanecki, R. et al. S-nitroso human serum albumin given after LPS challenge reduces acute lung injury and prolongs survival in a rat model of endotoxemia. Naunyn-Schmied Arch Pharmacol 379, 281–290 (2009). https://doi.org/10.1007/s00210-008-0351-2

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