Evaluating the role of inducible nitric oxide synthase using a novel and selective inducible nitric oxide synthase inhibitor in septic lung injury produced by cecal ligation and puncture

Citation
I. Okamoto et al., Evaluating the role of inducible nitric oxide synthase using a novel and selective inducible nitric oxide synthase inhibitor in septic lung injury produced by cecal ligation and puncture, AM J R CRIT, 162(2), 2000, pp. 716-722
Citations number
28
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Respiratory Systems","da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
ISSN journal
1073-449X → ACNP
Volume
162
Issue
2
Year of publication
2000
Pages
716 - 722
Database
ISI
SICI code
1073-449X(200008)162:2<716:ETROIN>2.0.ZU;2-K
Abstract
We studied the role of inducible nitric oxide synthase (iNOS) in septic lun g injury using a novel and selective iNOS inhibitor (a fused piperidine der ivative; ONO-1714) following a cecal ligation and puncture (CLP) procedure. All rats that received CLP died within 48 h after the intervention. The su bcutaneous injection of ONO-1714 at 0.03 mg/kg every 12 h resulted in a sig nificantly longer survival time than the saline control only when administr ation was started 12 h after the CLP procedure. The other administration sc hedules, which started immediately or 6 h after the intervention, did not s how any improvement in the survival rates in comparison with the saline con trol. The administration of ONO-1714 at higher (0.1 mg/kg) or lower (0.01 m g/kg) doses when given anytime after the intervention did not improve the s urvival rates. The NOx (NO2- divided by NO3-) levels in the plasma signific antly increased 12 h after intervention in comparison with NOx at 0 h and t hereafter further increased in parallel with the time elapsed. The CLP rats that were initially treated with ONO-1714 (0.03 mg/kg subcutaneously every 12 h) 12 h after intervention showed significantly reduced NOx levels in t he plasma in comparison with the saline control. The NO synthase activity i n lung homogenates increased from 6 to 24 h after the CLP and thereafter de creased to 42 h. The administration of ONO-1714 inhibited iNOS activity (un der calcium-free conditions) in preference to total iNOS activity (under ca lcium-dependent conditions) in lung homogenates, which thus suggested that this compound selectively inhibited iNOS in lung tissue. The iNOS protein e xpression in the lung and liver homogenates showed a similar time course wi th alterations of NOS activity, namely a maximum level at 24 h after the in tervention followed by decreasing levels to 42 h. On the other hand, other isozymes of NOS, eNOS, and nNOS in lung homogenates, were constantly expres sed over the time course after the CLP. Since the iNOS mRNA expression in l ung homogenates continued to elevate until 42 h, the decrease in iNOS activ ity and protein expression later than 24 h after the CLP was thus considere d to be due to some posttranscriptional mechanism during the late phase of sepsis. In conclusion, intervention with a potent and selective iNOS inhibi tor seemed to improve survival in CLP rats when used at the appropriate dos es and time points. However, the self-limited mechanism of iNOS regulation in the lungs may also indicate that iNOS plays only a limited role in sepsi s and septic shock.