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Nitric oxide (NO) is an endogenously produced vasodilator which modulates systemic and pulmonary blood flow through the actions of cyclic guanylate monophosphate (cGMP) on vascular smooth muscle.1-4 Non-haemodynamic properties of NO include the modulation of platelet inhibition, neurotransmission, hormone release, and cell growth. Under physiological circumstances the basal production of NO is regulated by constitutive forms of the enzyme NO synthase (cNOS). Under conditions of chemical and mechanical stress increased NO production is detectable, produced primarily via an inducible NOS isoform (iNOS).5 ,6
Evidence has accumulated that NO is implicated in the pathogenesis of sepsis and septic shock and may contribute to the development of multiple organ dysfunction. Firstly, iNOS has been isolated from human neutrophils in urinary sepsis7 and from alveolar macrophages in sepsis induced acute lung injury (ALI).8Secondly, NO is known to influence the inflammatory response through actions on both innate and adaptive immune systems.9Thirdly, non-specific cNOS and iNOS inhibition using novel pharmacological agents has been shown to improve systemic vascular resistance and survival in rodent models of sepsis.10 ,11
Despite such evidence, the exact role of NO in modulating the pathogenesis and clinical manifestations of pulmonary infection is far from clear. Moreover, the possibility that increased NO production has protective effects in such circumstances suggests that efforts to block its production may be counterproductive, particularly in patients with sepsis. Most research in this area has been performed in animal models, not least because levels of NOS products are in general higher than those measured in humans, and has produced evidence in favour of both possibilities.
A protective role for iNOS is apparent in genetically modified “knock out” mice unable to express iNOS which have an enhanced susceptibility to infection with a wide variety of lung pathogens including Chlamydia pneumoniae,12 Legionella pneumophila,13 andMycobacterium tuberculosis.14Moreover, the mortality of wild-type mice infected withStaphylococcus aureus is increased using the selective iNOS inhibitor aminoguanidine.15 In these models the production of iNOS appears to be tightly regulated by interferon (IFN)-gamma through the IFN regulatory factor IRF-1,16 ,17although regulation at the post-translational level of NOS activity may also account for differences in susceptibility to pulmonary infections.18 Moreover, NO derived from iNOS appears not only to have direct antimicrobial activity through the production of reactive nitrogen species such as peroxynitrite, but also an immunoregulatory role by modulating T cell responses.19 ,20
Evidence favouring a protective role for the iNOS-NO pathway in pulmonary infection has been countered by data from other studies. Thus, iNOS does not appear to modulate the response to infection in iNOS knock out mice infected with the Mycobacterium avium intracellulare complex.21 Secondly, in a model of viral pneumonia associated with iNOS upregulation and increased activity, NOS inhibition withl-N-monomethyl-arginine improved survival.22Thirdly, mice deficient in the iNOS gene are more resistant to developing ALI in response to Escherichia coliendotoxin.23
Information regarding the relationship of NOS, NO, and infection is also emerging from clinical studies. Human neutrophils stimulated with the cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-1, and IFN-γ express iNOS mRNA and protein,24 as do those from patients with urinary sepsis.7 Alveolar macrophages from patients with active pulmonary tuberculosis25 and sepsis induced acute respiratory distress syndrome (ARDS)8display similar properties. Increased iNOS expression in bronchoalveolar lavage fluid is associated with increased levels of exhaled NO from patients with active, untreatedMycobacterium tuberculosisinfection.26 By contrast, reduced levels of iNOS mRNA have been found in the bronchial epithelium of patients with cystic fibrosis, suggesting that the iNOS derived NO system plays a part in the susceptibility of these patients to bacterial colonisation.27
What can be concluded from these data? The body of evidence from investigations in animal models suggests increasingly that NO has both antimicrobial and immunoregulatory roles in infection. Although clinical studies have also demonstrated the upregulation of iNOS in the setting of sepsis, whether this represents an active role in modulating the immune response to infection or is merely a marker of inflammation is currently unknown. In addition, potentially deleterious “downstream” effects of increased NO production on vascular tone and tissue oxygenation cannot be ignored and inhibition of NOS in a recent clinical study has been shown to improve the haemodynamic consequences of sepsis.28 Clinical trials of the effects of iNOS inhibition on vascular tone in patients with hypotensive septic shock should therefore continue in parallel with laboratory based research into the therapeutic potential of NOS manipulation in pulmonary infection. We should not be blind to the possibility that the vasoregulatory effects of NO may prove to be equally or more significant than its antimicrobial or immunoregulatory properties.
Acknowledgments
SS is a British Heart Foundation Clinical Training Fellow. SJW is a Wellcome Trust Clinical Training Fellow.