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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Nitric oxide in trauma and sepsis

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NO plays an important role in hemorrhagic shock (HS), sepsis and infection. Adequate levels of NO production are necessary to preserve perfusion and ensure cytoprotective functions in HS and sepsis. NO overproduction appears to contribute to hemodynamic instability and tissue damage. These observations have led to the development of strategies to inhibit NO synthesis or scavenge excess NO in patients with septic or hemorrhagic shock.

The studies and experimental data presented in this review are based on pharmacologic studies in vivo using both selective iNOS inhibitors and NO scavengers. The novel observations are confirmed by results from studies with a genetic approach using iNOS deficient mice. Thus, the results convey a high level of confidence. No reliable data is published from human studies using selective iNOS inhibition or NO scavengers in HS or sepsis.

NO production

The free radical nitric oxide (NO) is synthesized from one of the two chemically equivalent guanidino groups of L-arginine and oxygen by a family of enzymes termed NO synthases (NOS). Three isoforms have been described and cloned (1): endothelial cell NOS (ecNOS, or type 3), brain NOS (bNOS, nNOS, or type 1), and inducible macrophage type NOS (iNOS, or type 2). The constitutive NO synthases (NOS 1 and NOS 3) produce NO in small amounts whereas the inducible NOS is responsible for the production of large amounts of NO.

NOS-2 typically only is expressed when cells are exposed to proinflammatory cytokines, microbial products (i.e. endotoxin, peptidoglycan, lipoteichoic acid), or hypoxia, constitutive NOS-2 expression has been observed in lung and small bowel epithelial cells. NOS-2 differs considerably in its pattern of expression and regulation than the constitutive isoforms. While NOS-3 is expressed in a limited number of cells, NOS-2 can be expressed in a wide variety of cell types, and its expression is regulated at tile level of transcription and iNOS mRNA stability. The basal release of NOS-3 generated NO maintains vasodilation in small resistance arteries in part through the guanylate cyclase/cGMP system in smooth muscle cells, leading to relaxation of the vessel wall. This basal release also reduces the adhesion of platelets and polymorphonuclear granulocytes (PMN) to the endothelium. In contrast, the sustained production of NOS-2 generated NO contributes to antimicrobial activities, tissue injury, or conversely tissue protection depending on the setting. NO can rapidly move from cell to cell independent of membrane channels or receptors and react with a wide array of molecular targets. NO has a short half-life due to its reactivity and therefore diffuses only short distances. NO is rapidly inactivated by hemoglobin which keeps the action of NO localized (2). The stable endproducts of nitric oxide oxidation are nitrite and nitrate.

Molecular targets

NO participates in cellular metabolism, signal transduction, and cellular toxicity and protection. Important targets are intracellular iron, iron-containing proteins and thiol groups resulting in modification of enzyme activity, protein function, and NO neutralization (3). NO also reacts with other oxygen radicals leading to the formation of secondary products that are more reactive and toxic than NO (4). A prime example is the formation of the strong oxidant peroxynitrite (ONOO-) following reaction of NO with superoxide anion (O2-). In contrast, NO formation protects cells from reactive oxygen intermediates (ROI) toxicity. NO can scavenge hydroxyl radical (OH-) and inhibit radical-induced chain propagation during lipid peroxidation.

Cytoprotection, cytotoxicity

NO exerts cytotoxic effects through enzyme inhibition, toxic radical formation, inactivation of metabolic pathways, damage to cell structures and proteins, DNA mutation, and alteration of gene expression. These mechanisms explain NO-mediated control and suppression of cell growth of microorganisms, tumor cells, or lymphocytes. The cytoprotective properties of NO include radical scavenging, inhibition of O2- release by inactivating NADPH oxidase, prevention of platelet aggregation and PMN adhesion, and controlled vasodilation to maintain tissue perfusion. NO is also an effective inhibitor of apoptosis (5) or programmed cell death in many cell types, including endothelial cells and hepatocytes.

Hemorrhagic shock

HS suppresses endothelial cell function leading to decreased synthesis of NOS-3, which results in decreased organ perfusion and increased platelet/neutrophil aggregation. Prolonged HS induces NOS-2 expression in various tissues and contributes to vascular decompensation and hyporeactivity to vasoconstrictor agents (6). In addition, induced NO promotes direct tissue damage through the formation of peroxynitrite and its associated toxicity, such as activation of poly ADP ribose synthase or PARS. NO and peroxynitrite have signaling functions which regulate cellular responses and serve as amplifier of the inflammatory cascade following HS. In conditions of redox stress such as HS, NO is able to activate intracellular redox-sensitive signaling pathways resulting in NF-κB activation. Intermediate steps may include NO-mediated activation of p21ras (7). We reported the essential role of induced NO for the initiation of the inflammatory response following HS characterized by activation of transcription factors NF-κBΚ and Stat3, increased cytokine production, PMN infiltration into tissues, and organ damage (8).


Septic shock is characterized by profound hypotension poorly responsive to fluid resuscitation and vasopressor therapy. Mediators of sepsis such as endotoxin or the inflammatory cytokines TNFα, IL-l, and IFγ (9) have been shown to induce iNOS expression in human studies as well as in animals models. Overproduction of the vasodilator NO contributes to hypotension and vascular hyporeactivity to vasoconstrictor agents. The time course of iNOS expression correlated with hypotension, PMN accumulation and cytokine induction in the pathogenesis of endotoxic shock. NOS inhibition increased blood pressure in animals challenged with endotoxin, TNFα, IL-1 and IL-2 (10). In addition, NO caused myocardial dysfunction and impaired cardiac output. In inflammation and infection NO promotes the inflammatory response by enhancing cytokine release, such as TNFα and IL-8, and activation of cyclooxygenase with increased formation of prostaglandins. Beneficial effects of NO include antimicrobial activity of macrophages against fungal, helminthic, protozoal, and bacterial pathogens. RBC can interfere with NO-mediated host defense system. The capacity of red blood cells and hemoglobin to scavenge cytotoxic oxygen and nitrogen radicals produced as part of the inflammatory response to intraperitoneal sepsis protects bacteria from oxidative bactericidal activity and accounts for the adjuvant effect of blood in peritonitis (11).

Therapeutic interventions

At physiologic concentrations NO is protective. Pulsatile blood flow is a potent stimulus of endothelium-derived NO production. NO provides necessary vasodilation to ensure organ perfusion, inhibits platelet and leukocyte aggregation, and participates in protein modification and cell signaling. During pathologic conditions, overexpression of NO exposes the environment to the toxic potential of NO with toxic radical formation, protein inhibition and DNA damage (12).

Administration of non-selective NOS inhibitors reduced blood flow to most organs and promoted adhesion and activation of platelets and granulocytes. Inhibition of endothelial NO production induces microvascular disruption. These observation indicate that interference with the ecNOS activity has deleterious effects. Induction of iNOS may have either toxic or protective effects. Factors which appear to dictate the consequences of iNOS expression include type of insult, tissue type, level and duration of iNOS expression and redox state of the tissue. Induction of iNOS causes endothelial injury, inhibits cellular respiration and can lead to cell dysfunction and cell death. In dear contrast, expression of iNOS in liver cells protected from endotoxin and TNFα-induced toxicity (13). Overexpression of iNOS using gene transfer limited LPS-induced toxicity in endothelial cells. In the treatment of pulmonary hypertension and ARDS inhaled NO has yielded promising results. NO inhalation reduced pulmonary artery pressure, and ventilation-perfusion mismatch probably through increasing selected perfusion of ventilated alveoli and anti-inflammatory effects of NO (14). Inhaled NO may also exert systemic effects since experimental studies have shown that inhaled NO reduces ischemia/reperfusion induced damage at remote sites (15).

The controversial reports and the apparent paradoxes in the literature on the effect of NO in sepsis and HS are due to the different experimental models used. In HS, the use of selective iNOS inhibitors provided beneficial effects including increase in cardiac output, renal blood flow and glomerular filtration rate, protection against development of gastric lesions and protection against organ injury and improved survival (12). In sepsis, NOS inhibitors cause an immediate rise in blood pressure and vascular resistance. However, high doses of non-selective NOS inhibitors that also interfere with ecNOS increased the incidence of organ ischemia, microvascular thrombosis, and mortality (16). In contrast, selective iNOS inhibition alter LPS challenge had beneficial effects by reducing bacterial translocation and intestinal damage, attenuated organ injury, reversed hypotension and circulatory failure, and improved survival (17). These results suggest that maintenance of vascular perfusion by ecNOS plays a protective role in septic shock whereas iNOS is responsible for vascular decompensation and tissue damage. iNOS specific NOS inhibition might reduce the circulatory failure and tissue toxicity associated with excessive NO production without the Consequences of ecNOS inhibition.


Non-selective NOS inhibition is not desirable in shock. Inadequate or excessive NO production is ultimately harmful to the host resulting in hypercoagulopathy, altered perfusion, uncontrolled infection, tissue injury, and hypotensive shock. Appropriate amounts of NO as part of the inflammatory response result in host survival. The use of iNOS inhibitors would allow for blocking of self-amplifying circles of inflammation in the early phases of sepsis and shock. In conclusion non-specific iNOS inhibition or high-dose inhibition with impairment of both the ecNOS and iNOS isoforms, routinely results in tissue damage and deleterious outcomes, whereas specific iNOS inhibition or lower dose inhibition tends to have protective effects suggesting that ecNOS is protective and that iNOS may be toxic or protective depending on the setting.

Another attractive therapeutic alternative is the use of NO scavengers that remove only the excess NO regardless of source thereby preserving essential basal levels of NO required to maintain vasodilation and vasoprotection but suppressing NO-mediated toxicity.


Geller D A, Billiar # B L #. Molecular biology of nitric oxide synthases. TR Cancer Metastasis Rev. (1998);17:7–23. [PubMed: 9544420]
Tzeng E, Billiar T R. Nitric oxide and the surgical patient. Identifying therapeutic targets. Arch Surg. (1997);132:977–982. [PubMed: 9301610]
Stamler J S, Singel D J, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science. (1992);258:1898–1902. [PubMed: 1281928]
Crow J P, Beckman J S. Reactions between nitric oxide, superoxide, and peroxynitrite: footprints of peroxynitrite in vivo. Adv Pharmacol. (1995);34:17–43. [PubMed: 8562432]
Mannick J B, Asano K, Izumi K, Kieff E, Stamler J S. Nitric oxide produced by Human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell. (1994);79:1137–1146. [PubMed: 7528106]
Thiemermann C, Szabo C, Mitchell J A, Vane J R. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci USA. (1993);90:267–271. [PMC free article: PMC45641] [PubMed: 7678341]
Lander H M, Hajjar D P, Hempstead B L, Mirza U A, Chait B T, Campbell S, Quilliam L A. A molecular redox switch on p21(ras). Structural basis for the nitric oxide-p21(ras) interaction. J Biol Chem. (1997);272:4323–4326. [PubMed: 9020151]
Hierholzer C, Harbrecht B, Menezes J M, Kane J, MacMicking J, Nathan C F, Peitzman A B, Billiar T R, Tweardy D J. Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med. (1998);187:917–928. [PMC free article: PMC2212185] [PubMed: 9500794]
Morris S M Jr, Billiar T R. New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol. (1994);266:E829–E839. [PubMed: 8023911]
Thiemermann C. The role of the L-arginine: nitric oxide pathway in circulatory shock. Adv Pharmacol. (1994);28:45–79. [PubMed: 7521665]
Kim Y M, Hong S J, Billiar T R, Simmons R L. Counterprotective effect of erythrocytes in experimental bacterial peritonitis is due to scavenging of nitric oxide and reactive oxygen intermediates. Infect Immun. (1996);64:3074–3080. [PMC free article: PMC174190] [PubMed: 8757836]
Szabo C, Thiemermann C. Invited opinion: role of nitric oxide in hemorrhagic, traumatic, and anaphylactic shock and thermal injury. Shock. (1994);2:145–155. [PubMed: 7537167]
Ou J, Carlos T M, Watkins S C, Saavedra J E, Keefer L K, Kim Y M, Harbrecht B G, Billiar T R. Differential effects of nonselective nitric oxide synthase (NOS) and selective inducible NOS inhibition on hepatic necrosis, apoptosis, ICAM-1 expression, and neutrophil accumulation during endotoxemia. Nitric Oxide. (1997);1:404–416. [PubMed: 9441911]
Weitzberg E, Rudehill A, Lundberg J M. Nitric oxide inhalation attenuates pulmonary hypertension and improves gas exchange in endotoxin shock. Eur J Pharmacol. (1993);233:85–94. [PubMed: 8472750]
Fox-Robichaud A, Payne D, Hasan S U, Ostrovsky L, Fairhead T, Reinhardt P, Kubes P. Inhaled NO as a viable antiadhesive therapy for ischemia/reperfusion injury of distal microvascular beds. J Clin Invest. (1998);101:2497–2505. [PMC free article: PMC508839] [PubMed: 9616221]
Nava E, Palmer R M, Moncada S. Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? Lancet. (1991);338:1555–1557. [PubMed: 1683974]
Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet. (1991);338:1557–1558. [PubMed: 1720856]
Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6909


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