Endotoxin-induced acute lung injury and organ dysfunction are attenuated by pentobarbital anaesthesia.
1. Acute lung injury (ALI) as a result of sepsis is a major cause of mortality. Certain anaesthetic agents have been reported to suppress pro-inflammatory cytokines and inducible nitric oxide (NO) synthase (iNOS) activities. We investigated the effects of pentobarbital on ALI and organ functions after the administration of endotoxin. 2. Intravenous (i.v.) pentobarbital (20 or 40 mg/kg) was administered 5 min after lipopolysaccharide (LPS; 10 or 30 mg/kg via i.v. infusion). To avoid hypoxia and/or hypercapnia following anaesthesia, we installed a special chamber connected to a rodent ventilator to provide ventilation with 95% oxygen content and 5% nitrogen. The animal was kept at eucapnic conditions (arterial PCO2 at an average of 38 +/- 2 mmHg). 3. We monitored the arterial pressure (AP) and heart rate (HR). Acute lung injury was evaluated by lung weight changes, protein concentration in bronchoalveolar lavage, and Evans blue leakage. Plasma nitrate/nitrite, methyl guanidine and biochemical factors were determined. Pathological and immunofluorescent examinations were performed to observe the lung changes and to determine the activities of pro-inflammatory cytokines, nitrotyrosine and iNOS. 4. Lipopolysaccharide caused dose-dependent systemic hypotension with an increase in the extent of ALI. The lung pathology included oedema and inflammatory cell infiltration. Accompanying the ALI, LPS elevated plasma nitrate/nitrite, methyl guanidine, blood urea nitrogen, lactic dehydrogenase, creatinine phosphokinase, glutamic transaminase and amylase. The lung tissue content of tumour necrosis factor-alpha, interleukin-lbeta, iNOS and nitrotyrosine was increased following LPS administration. These changes were abrogated by pentobarbital anaesthesia. 5. Our results indicated that pentobarbital anaesthesia significantly augmented the LPS-induced systemic hypotension. However, it attenuated the LPS-induced ALI and organ dysfunctions. This agent also improved the survival rate following LPS at high and low doses. This mechanism may be related to the inhibitory effects on the increases in the production or activity of NO, free radicals, pro-inflammatory cytokines, nitrotyrosine and iNOS.
Kao
Shang-Jyh
SJ
School of Respiratory Therapy, Fu-Jen Catholic Medical College and Taipei Medical University, Taiwan.
Su
Chain-Fa
CF
Liu
Demeral D
DD
Chen
Hsing I
HI
D000771:Anesthesia, Intravenous; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D007262:Infusions, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D015846:Monokines / Q000378:metabolism; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D010424:Pentobarbital / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D004731:Endotoxins; D006993:Hypnotics and Sedatives; D008070:Lipopolysaccharides; D015846:Monokines; D009566:Nitrates; D009573:Nitrites; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D010424:Pentobarbital