Inhibition of inducible nitric oxide synthase prevents LPS-induced acute lung injury in dogs

First Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan.
The Journal of Immunology (Impact Factor: 4.92). 03/1998; 160(6):3031-7.
Source: PubMed


Nitric oxide (NO) is produced by inducible NO synthase (iNOS) after LPS stimulation, and reacts with superoxide to form peroxynitrite. We hypothesize that in LPS-induced lung injury, NO generated by iNOS plays a key role through the formation of peroxynitrite. We developed an acute lung injury dog model by injecting LPS, and examined the effects of selective iNOS inhibitors, aminoguanidine (AG) and S-methylisothiourea sulfate (SMT), on the LPS-induced lung injury. At 24 h after LPS injection, arterial oxygen tension and mean arterial pressure decreased, and shunt ratio and lung wet-to-dry weight ratio increased. On histology, the LPS group had marked neutrophil infiltration and widening of the alveolar septa. On immunohistochemistry, iNOS and nitrotyrosine, a major product of nitration of protein by peroxynitrite, were observed in the interstitium, capillary wall, and neutrophils in the airspaces of the LPS group. Treatments with AG and SMT prevented worsening of gas exchange, hemodynamics, and wet-to-dry weight ratio. On histology, AG and SMT treatments markedly suppressed lung injury, iNOS protein, and nitrotyrosine production. We conclude that NO released by iNOS may play a critical role in the pathogenesis of LPS-induced acute lung injury. This study suggests that iNOS inhibitors may have potential in the treatment of LPS-induced acute respiratory distress syndrome.

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    • "ischemic-ventilated lung may lead to an inflammatory process that upregulates iNOS. This process is expected to exaggerate during the reperfusion stage, carrying macrophages, platelets, and leucocytes , which synthesize iNOS and superoxide [29]. Our data is in consistence with the results reported by Sedoris et al., that IR upregulates inducible nitric oxide synthesis and/activity, which coincides with reduced endothelial nitric oxide synthase activity as suggested by its uncoupling and may contribute to ischemia–reperfusion-induced pulmonary vasocon- striction. "
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    ABSTRACT: Background: Pulmonary ischemia-reperfusion (IR) is a biopathological event detectable in several clinical conditions, including lung transplantation, cardiopulmonary bypass, resuscitation, and pulmonary embolism. The understanding behind the activation of various inflammatory mediators regulating the apoptotic pathways remains largely unknown. We investigated the temporal expression of endothelial nitric oxide (eNOS), inducible (iNOS), and cyclooxygenase-2 (COX-2) proteins following lung-IR injury. Methods: Lung IR was induced in anesthetized rats. One hour ischemia was performed by clamping the left hilum. eNOS, iNOS, and COX-2 levels in the bronchoalveolar lavage (BAL) were measured at different time points after restoring lung perfusion in conjunction with histological changes and cellular apoptosis. Results: BAL-eNOS levels were increased as early as 3 hours post IR, attaining the highest values (5.5 U/mL) at 3 hours, compared to non-IR values (2.8 U/mL). BAL-iNOS increased at 3-hour post-IR (3 U/mL). iNOS reached the highest levels at 24 hours (4.5 U/mL) as compared to nonischemic lungs (1.8 U/mL). COX-2 peaked at 12 hours (.025 U/mL) compared to 3, 24, and 48 hours. Highest apoptotic rates were detected at 12 and 48 hours following IR. Conclusions: The time-associated involvement of eNOS, iNOS, and COX-2 enzymes during the evolution of IR injury may point to an early reaction of the NOSs system versus the COX-2. Similar patterns of enzymatic activity were previously shown in the context of lung IR injury. This temporal activation may indicate an involvement of eNOS in an early reparative response, and possibly the late-pathological response, mediated by the coinduction of iNOS-COX-2.
    Experimental Lung Research 12/2013; DOI:10.3109/01902148.2013.858196 · 1.41 Impact Factor
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    • "S-methylisothiourea (SMT) is a NOS inhibitor and possesses moderate degree of selectively in inhibiting the inducible isozymes over the constitutive . SMT, a preferential iNOS inhibitor improved the survival in rodent models of sepsis due to lipopolysaccharide (Aranow et al., 1996: Szabo et al., 1994) and attenuated the endotoxemia-induced lung injury (Numata et al., 1998) and pulmonary edema (Arkovitz et al., 1996). "

    Pharmacology Biochemistry and Behavior 01/2013; 103(4):764-772. · 2.78 Impact Factor
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    • "SMT has been demonstrated to improve survival in rodent models of sepsis due to lipopolysaccharide (LPS) (Aranow et al. 1996). SMT has also been found to attenuate the endotoxemia-induced lung injury (Numata et al. 1998) and pulmonary edema (Arkovitz et al. 1996). SMT protects animals from blood circulation disturbances and organ dysfunction caused by endotoxins and increases the survival rate upon the septic shock (Szabo et al. 1994). "
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    ABSTRACT: Much information is available on the role of nitric oxide (NO) in osteoarthritis (OA). However, its role has not been studied in the monosodium iodoacetate (MIA)-induced model of osteoarthritic pain. The present study was undertaken in rats to investigate the effect of iNOS inhibitor s-methylisothiourea (SMT) in MIA-induced osteoathritic pain and disease progression in rats. Osteoarthritis was produced by single intra-articular injection of the MIA in the right knee joint on day 0. Treatment groups were orally gavazed with different doses of SMT (10, 30 and 100 mg/kg) and etoricoxib (10 mg/ Kg) daily for 21 days. On days 0, 3, 7, 14 and 21, pain was measured and histopathology of right knee joint was done on day 21. SMT produced analgesia in a dose-dependent manner as shown by mechanical, heat hyperalgesia, knee vocalization, knee squeeze test, and spontaneous motor activity test. SMT reduced NO production in synovial fluid. Histopathological findings indicated that SMT reduced disease progression as evident from complete cartilage formation in rats treated with SMT at 30 mg/Kg. In conclusion, the results indicate that SMT attenuates the MIA-induced pain and histopathological changes in the knee joint. The antinociceptive and antiarthritic effects of SMT were mediated by inhibiting cartilage damage and suppression of NO in synovial fluid. It is suggested that SMT has potential as a therapeutic modality in the treatment of osteoarthritis.
    Pharmacology Biochemistry and Behavior 12/2012; 103(4). DOI:10.1016/j.pbb.2012.12.013 · 2.78 Impact Factor
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