Published ahead of print on October 11, 2004, doi:10.1164/rccm.200302-305OC
Am. J. Respir. Crit. Care Med., Volume 171, Number 2, January 2005, 147-157
A more recent version of this article appeared on January 15, 2005
Submitted on February 28, 2003
Accepted on October 1, 2004
Hypercapnia via Reduced Rate and Tidal Volume Contributes to Lipopolysaccharide-induced Lung Injury
John D Lang, Jr1*, Mario Figueroa2, K. David Sanders3, Mutay Aslan2, Yuliang Liu2, Phillip Chumley2, and Bruce A Freeman4
1 Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, AL, USA; The Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL, USA,
2 The Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, AL, USA,
3 Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, AL, USA,
4 Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pharmacology, The University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: john.lang{at}ccc.uab.edu.
Appreciating that carbon dioxide (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 ~7 ml/kg tidal volume for 6 hours. Animals were randomized to one of the following conditions: eucapnia (PaCO2 ~ 35 - 40 mm Hg); eucapnia + LPS; eucapnia + LPS + inhaled nitric oxide (iNO delivered at ~20 ppm; hypercapnia (PaCO2 ~ 60 mm Hg); hypercapnia + LPS; hypercapnia + LPS + iNO. The hypercapnia + LPS groups compared with groups exposed to eucapnia + LPS displayed significantly increased BALF protein concentrations (p < 0.05), lung wet - to - dry ratios (p < 0.05), BALF cell counts (p < 0.05), and lung histologic alterations consistent with greater injury. Furthermore, expression of NOS(2) (p < 0.05), tissue MPO 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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