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Published ahead of print on October 11, 2004, doi:10.1164/rccm.200302-305OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 147-157, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200302-305OC

Original Article

Hypercapnia via Reduced Rate and Tidal Volume Contributes to Lipopolysaccharide-induced Lung Injury

John D. Lang, Mario Figueroa, K. David Sanders, Mutay Aslan, Yuliang Liu, Phillip Chumley and Bruce A. Freeman

Departments of Anesthesiology and Biochemistry and Molecular Genetics, and The Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, Alabama

Correspondence and requests for reprints should be addressed to John D. Lang, Jr., M.D., The University of Alabama at Birmingham, Department of Anesthesiology, 845 Jefferson Tower, 619 South 19th Street, Birmingham, AL 35233–6810. E-mail: john.lang{at}ccc.uab.edu

Appreciating that CO2 modifies the chemical reactivity of nitric oxide (NO)–derived inflammatory oxidants, we investigated whether hypercapnia would modulate pulmonary inflammatory responses. Rabbits (n = 72) were ventilated with approximately 7-ml/kg tidal volume for 6 hours. Animals were randomized to one of the following conditions: eucapnia (PaCO2 at approximately 35–40 mm Hg), eucapnia + lipopolysaccharide (LPS), eucapnia + LPS + inhaled NO (iNO delivered at approximately 20 ppm), hypercapnia (PaCO2 at approximately 60 mm Hg), hypercapnia + LPS, and hypercapnia + LPS + iNO. The hypercapnia + LPS groups compared with groups exposed to eucapnia + LPS displayed significantly increased bronchoalveolar lavage fluid protein concentrations (p < 0.05), lung wet-to-dry ratios (p < 0.05), bronchoalveolar lavage fluid cell counts (p < 0.05), and lung histologic alterations consistent with greater injury. Furthermore, expression of inducible nitric oxide synthase (p < 0.05), tissue myeloperoxidase content (p < 0.05), and formation of lung protein 3-nitrotyrosine derivatives (p < 0.05) was greatest under conditions of hypercapnia + LPS. Groups exposed to hypercapnic conditions without LPS did not manifest these changes. The inhalation of iNO attenuated selected indices of lung injury. We conclude that hypercapnia induced by means of reduced rate and tidal volume amplifies pulmonary inflammatory responses.

Key Words: carbon dioxide • low tidal volume ventilation • lung injury




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