Relative Contribution of Hemopoietic and Pulmonary Parenchymal Cells to Lung Inducible Nitric Oxide Synthase (iNOS) Activity in Murine Endotoxemia

Wang, L.F.; Mehta, Sanjay; Weicker, Sean; Scott, Jeremy A.; Joseph, Mariamma; Razavi, Habib Moshref; McCormack, David G.

doi:10.1006/bbrc.2001.4842

Cited by 36 publications

(32 citation statements)

References 18 publications

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“…to the increased NOS2 production in lungs after the injection of LPS (52). In a subsequent publication, the same group further defines that the injury leading to microvascular leakage of proteins is caused by NOS2 produced by bone marrow-derived inflammatory cells (51).…”

Section: Nos2-expressing Inflammatory Cells In the Lung Parenchymamentioning

confidence: 96%

Effects of Acute Hypoxia and Lipopolysaccharide on Nitric Oxide Synthase-2 Expression in Acute Lung Injury

Agorreta

Garayoa²,

Montuenga³

et al. 2003

Am J Respir Crit Care Med

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The potential role of nitric oxide synthase-2 (NOS2) in acute lung injury (ALI) has gained increasing attention. This study evaluates the effects of hypoxia, an important feature of ALI, on NOS2 expression in a rat model of ALI caused by exposure to hypoxia and LPS. Exposure to hypoxia alone had no effect on the expression of NOS2 in rat lungs. LPS treatment resulted in a significant increase in NOS2 in the lungs, which was further enhanced by concomitant exposure to hypoxia. Immunohistochemical analysis and in situ hybridization showed no changes in the expression of NOS2 in lung resident cells under any conditions. The increase in NOS2 levels is mainly due to the influx of NOS2-expressing inflammatory cells. By morphologic analysis, these inflammatory cells were identified as neutrophils, lymphocytes, and monocytes. In vitro experiments of lung epithelial and endothelial cell lines showed no detectable expression of NOS2 with any of the treatments. In a macrophage cell line, LPS-induced NOS2 expression was not affected by the concomitant exposure to hypoxia. In conclusion, LPS increases NOS2 expression in rat lungs through the recruitment of NOS2-producing leukocytes. Simultaneous exposure to LPS and hypoxia results in a greater influx of inflammatory cells that further enhances NOS2 expression.Keywords: acute respiratory distress syndrome; endotoxin; leukocytes; sepsis Nitric oxide (·NO) is a multifunctional, short-lived gas that may contribute to toxic free radical production and potentiate lung injury. ·NO is synthesized by a family of enzymes called nitric oxide synthases (NOS). There are three NOS isoforms, namely, NOS1 (neuronal NOS), NOS2 (inducible NOS), and NOS3 (endothelial NOS). These isoenzymes were first purified from rat brain (1), murine macrophages (2), and bovine aortic endothelial cells (3), respectively. NOS enzymes are classically classified as either constitutive (NOS1 and NOS3) or inducible (NOS2), although it is now known that the expression of NOS1 and NOS3 can be induced (4), and that NOS2 is constitutively expressed in numerous cell types (5). The so-called constitutive isoforms (NOS1 and NOS3) release low amounts of ·NO and their activity is dependent on calcium and calmodulin (6). On the other hand, NOS2 produces large amounts of ·NO after induction by stimuli such as endotoxin and inflammatory cytokines (7-9). All three isoenzymes have been found in the lung (10-12) and mediate a wide variety of biological events in the respiratory system, (Received in original form September 11, 2002; accepted in final form May 16, 2003) Supported by the Spanish Ministry of Health (FIS 00/0698 and RTIC C03/10) and the Fundació n Echébano.Correspondence and requests for reprints should be addressed to Javier J. Zulueta, M.D., Pulmonary Medicine Service, Clínica Universitaria de Navarra, University of Navarra, Avenida Pío XII, 36, 31008 Pamplona, Spain. E-mail: jzulueta@unav.es This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals...

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Section: Nos2-expressing Inflammatory Cells In the Lung Parenchymamentioning

confidence: 96%

Effects of Acute Hypoxia and Lipopolysaccharide on Nitric Oxide Synthase-2 Expression in Acute Lung Injury

Agorreta

Garayoa²,

Montuenga³

et al. 2003

Am J Respir Crit Care Med

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“…Evidence supports both the airway epithelial cells and inflammatory cells as key contributors of NO in models of lung inflammation and lung injury (Wang et al, 2001;Hickey et al, 2002;Razavi et al, 2004). Using chimeric NOS2 mice, Wang and colleagues showed that the majority of NO exhaled after LPS injection into the tail vein, as measured by serum levels of NO X , was produced primarily by lung parenchymal cells (Wang et al, 2001). In contrast, a recent paper by this same group also using the chimeric NOS2 model, but this time after cecal perforation in mice, showed that NO generated by NOS2 in the neutrophils was primarily responsible for modulating neutrophilic migration into the lung (Razavi et al, 2004).…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

“…Chimeric NOS2 strains (NOS2 +/−, NOS2 −/+) of mice were developed using techniques described previously (Scott et al, 2002;Wang et al, 2001). In brief, we began with C57BL/6 (NOS2+/+) and NOS2 knockout (NOS2−/−) mice.…”

Section: Bone Marrow Transplantation and Chimera Developmentmentioning

confidence: 99%

“…This approach is well established (Scott et al, 2002;Wang et al, 2001); for example, it has been used to study a murine model of sepsis. This approach allows us to ask whether changing the genotype of selected cell populations in an animal (in our case the presence or absence of NOS2 in the inflammatory cells) affects the response of a target organ, e.g.…”

Section: Introductionmentioning

confidence: 99%

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Differentiation of the roles of NO from airway epithelium and inflammatory cells in ozone-induced lung inflammation

Kenyon

Eiserich

Morrissey

et al. 2006

Toxicology and Applied Pharmacology

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Mice lacking inducible nitric oxide synthase (NOS2−/−) are more susceptible to ozone-induced lung inflammation and injury than their isogenic wild-type (NOS2+/+) counterparts, demonstrating an apparent protective effect for NOS2 in murine lungs. We hypothesized that nitric oxide (NO) generated from either NOS2 in the airway epithelial cells or the bone marrow-derived inflammatory cells was responsible for the protective effect of NOS2. To test this hypothesis, we prepared chimeric mice by killing their endogenous bone marrow cells by whole body irradiation, followed by bone marrow transplantation from a heterologous donor mouse. We exposed C57BL/6 (NOS2+/+), NOS2 −/−, and chimeric NOS2 mice (NOS2−/+, NOS2+/−) to 1 ppm of ozone for 3 consecutive nights. NOS2−/− mice were more severely injured after exposure to ozone than C57BL/6 mice, including a more robust inflammatory cell influx (4.14×10 5 ±2.19×10 5 vs. 2.78 ×10 5 ± 1.36×10 5 cells respectively; p=0.036) and greater oxidation of total protein sulfhydryls (R-SH) in their blood plasma. Chimeric NOS2 −/+ mice, which had bone marrow from NOS2−/− mice transplanted into C57BL/ 6 recipients, had a significantly greater response to ozone (increased numbers of neutrophils in lung lavage and decreased concentrations of exhaled NO) as compared to the reciprocal chimeric strain (NOS2+/−). We conclude that NOS2 has a protective effect against acute lung injury caused by ozone inhalation, which may be mediated, in part, by NO generated by NOS2 from inflammatory cells, predominantly neutrophils, recruited into the lung.

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Pathophysiology of Sepsis: The Role of Nitric Oxide

Finney¹,

Evans²

The Sepsis Text

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Relative Contribution of Hemopoietic and Pulmonary Parenchymal Cells to Lung Inducible Nitric Oxide Synthase (iNOS) Activity in Murine Endotoxemia

Cited by 36 publications

References 18 publications

Effects of Acute Hypoxia and Lipopolysaccharide on Nitric Oxide Synthase-2 Expression in Acute Lung Injury

Effects of Acute Hypoxia and Lipopolysaccharide on Nitric Oxide Synthase-2 Expression in Acute Lung Injury

Differentiation of the roles of NO from airway epithelium and inflammatory cells in ozone-induced lung inflammation

Pathophysiology of Sepsis: The Role of Nitric Oxide

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