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Published ahead of print on September 4, 2003, doi:10.1164/rccm.200205-394OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 1, January 2004, 46-56

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Submitted on May 5, 2002
Accepted on August 28, 2003

Hypercapnic acidosis attenuates endotoxin-induced acute lung injury

John G Laffey1*, Dave Honan2, Natalie Hopkins3, Jean-Marc Hyvelin3, John F Boylan2, and Paul McLoughlin3

1 Physiology, Conway Institute of Biomolecular and Biomedical Research and Dublin Molecular Medicine Centre, University College Dublin, Dublin, Ireland; Anaesthesia, Intensive Care and Pain Medicine, St. Vincent's University Hospital, Dublin, Ireland, 2 Anaesthesia, Intensive Care and Pain Medicine, St. Vincent's University Hospital, Dublin, Ireland, 3 Physiology, Conway Institute of Biomolecular and Biomedical Research and Dublin Molecular Medicine Centre, University College Dublin, Dublin, Ireland

* To whom correspondence should be addressed. E-mail: j.laffey{at}ireland.com.

Deliberate induction of prophylactic hypercapnic acidosis protects against lung injury following in vivo ischemia reperfusion and ventilation-induced lung injury. However the efficacy of hypercapnic acidosis in sepsis, the commonest cause of clinical ARDS, is not known. We investigated whether hypercapnic acidosis - induced by adding CO2 to inspired gas - would be protective against endotoxin-induced lung injury in an in vivo rat model. Prophylactic institution of hypercapnic acidosis, i.e. induction prior to endotoxin instillation, attenuated the decrement in arterial oxygenation, improved lung compliance and attenuated alveolar neutrophil infiltration compared to control conditions. Therapeutic institution of hypercapnic acidosis, i.e. induction following endotoxin instillation, attenuated the decrement in oxygenation, improved lung compliance, and reduced alveolar neutrophil infiltration and histologic indices of lung injury. Therapeutic hypercapnic acidosis attenuated the endotoxin-induced increase in the higher oxides of nitrogen and nitrosothiols in the lung tissue and epithelial lining fluid. Lung epithelial lining fluid nitrotyrosine concentrations were increased with hypercapnic acidosis. We conclude that hypercapnic acidosis attenuates acute endotoxin-induced lung injury, and is efficacious both prophylactically and therapeutically. The beneficial actions of hypercapnic acidosis were not mediated by inhibition of peroxynitrite-induced nitration within proteins.
Key words: Sepsis, Endotoxin, Multiple Organ Dysfunction Syndrome, Rat, ARDS, Nitric Oxide




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