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Effects of endothelin receptor antagonism on acute lung injury induced by chlorine gas
Östergötlands Läns Landsting, Centre for Teaching and Research in Disaster Medicine and Traumatology, Centre for Teaching and Research in Disaster Medicine and Traumatology. Linköping University, Faculty of Health Sciences.
Östergötlands Läns Landsting, Centre for Teaching and Research in Disaster Medicine and Traumatology, Centre for Teaching and Research in Disaster Medicine and Traumatology. Linköping University, Faculty of Health Sciences.
Östergötlands Läns Landsting, Centre for Teaching and Research in Disaster Medicine and Traumatology, Centre for Teaching and Research in Disaster Medicine and Traumatology. Linköping University, Faculty of Health Sciences.
Östergötlands Läns Landsting, Centre for Teaching and Research in Disaster Medicine and Traumatology, Centre for Teaching and Research in Disaster Medicine and Traumatology. Linköping University, Faculty of Health Sciences.
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2006 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 34, no 6, 1731-1737 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To test the hypothesis that the endothelin system is involved in chlorine gas-induced lung injury.

DESIGN: Experimental study.

SETTING: Academic research laboratory.

SUBJECTS: Twenty-four domestic juvenile pigs.

INTERVENTIONS: Anesthetized, ventilated pigs were exposed to chlorine gas (400 parts per million in air) for 20 mins and then randomly allocated to four groups (n = 6 in each group). The tezosentan pretreatment group received the dual endothelin receptor antagonist tezosentan 20 mins before and hyperoxic gas (Fio2 0.6) after chlorine gas exposure. The tezosentan postinjury treatment group received hyperoxic gas after chlorine gas exposure and tezosentan 60 mins later. Animals in the oxygen group received hyperoxic gas after chlorine gas exposure. Pigs in the fourth group (air) were ventilated with room air (Fio2 0.21) throughout the experiment.

MEASUREMENTS AND MAIN RESULTS: Hemodynamics, gas exchange, lung mechanics, and plasma endothelin-1 were evaluated for 6 hrs. Chlorine gas exposure induced an increase in circulating endothelin-1 by 90% (p < .05). The acute chlorine gas-induced rise in pulmonary vascular resistance was partly blocked by tezosentan pretreatment (p < .001). Tezosentan postinjury treatment also decreased pulmonary vascular resistance to levels significantly lower than in the air and oxygen groups (p < .001). Recovery of peak airway pressure was better in the tezosentan-treated groups than in the air group. There were significant linear relationships between circulating endothelin-1 and pulmonary vascular resistance (r = .47, p < .001) and endothelin-1 and peak airway pressure (r = .41, p < .001). These relationships were modified by tezosentan.

CONCLUSIONS: Tezosentan modified chlorine gas-induced pulmonary dysfunction, indicating that the endothelin system is involved in this mode of acute lung injury.

Place, publisher, year, edition, pages
2006. Vol. 34, no 6, 1731-1737 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-37843DOI: 10.1097/01.CCM.0000218815.46611.63Local ID: 39627OAI: oai:DiVA.org:liu-37843DiVA: diva2:258692
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2012-10-26Bibliographically approved
In thesis
1. Pathophysiology and treatment of chlorine gas-induced lung injury: an experimental study in pigs
Open this publication in new window or tab >>Pathophysiology and treatment of chlorine gas-induced lung injury: an experimental study in pigs
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One of the most threatening scenarios in disaster medicine is the accidental release of toxic gases with the exposure of many people. In this respect, chlorine gas remains a significant threat due to its abundant use and transport through densely populated areas in modem society. Access to a simple and effective method of treatment that could be started early would be of great value. The main purpose of this study was to test a series of hypotheses related to chlorine gas lung injury and its treatment.

Anesthetized and mechanically ventilated pigs were exposed to chlorine gas (400 parts per million in air) using a closed system with a ventilator connected to gas cylinders. Plasma endothelin-1 (ET -1) and pro inflammatory cytokines were evaluated for 5 hours after injury while hemodynamics, gas exchange and lung mechanics were followed for 23 hours. Histopathology and lung water balance were assessed at the end of the experiment.

Chlorine gas exposure induced a rise in circulating ET-1 and circulating cytokines (TNF-α, and IL-1ß, IL-6). Pretreatment or treatment with tezosentan, a potent dual endothelin receptor antagonist, reduced the deterioration of pulmonary function induced by chlorine gas inhalation. Immediate prone positioning after chlorine gas injury not only inhibited deterioration of gas exchange but was also associated with improved pulmonary function and oxygen transport. Nebulized budesonide given within 30 minutes after chlorine gas lung injury was effective in preventing further progression of lung dysfunction but the effect of treatment given beyond 60 minutes was less efficient. The positive effects on pulmonary function and lung water were similar whether corticosteroids were given by aerosol or intravenously. Combined treatment with nebulized terbutaline and budesonide was associated with better recovery of lung function than either drug alone.

In conclusion, these studies outline the early pathophysiology of chlorine gas injury. They show that the endothelin system mediates the early pulmonary hypertensive and also to some extent the brochoconstrictive responses to inhaled chlorine gas. The work supports early administration of corticosteroids and ß2-agonists for individuals that are exposure to chlorine gas. In addition, early prone positioning of patients with severe chlorine gas lung injury may be useful.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2004. 53 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 877
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24066 (URN)3625 (Local ID)91-7373-853-0 (ISBN)3625 (Archive number)3625 (OAI)
Public defence
2004-12-20, Aulan, Katastrofmedicinskt Centrum, Hälsouniversitetet, Linköping, 13:00 (Swedish)
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Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-26Bibliographically approved

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Wang, JianpuOldner, A.Winskog, C.Edston, ErikWalther, Sten

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