Submitted on September 13, 2007
Accepted on November 7, 2007
Airway Smooth Muscle Relaxation is Impaired in Mice Lacking the p47phox Subunit of NAD(P)H Oxidase
Pasquale Chitano1*, Lu Wang2, Stanley N Mason2, Richard L Auten2, Erin N Potts3, William M Foster3, Anne Sturrock4, Thomas P. Kennedy5, John R Hoidal6, and Thomas M. Murphy7
1 Pediatrics / Pulmonary Diseases, Duke University Medical Center, Durham, North Carolina, United States
2 Pediatrics, Duke University Medical Center, Durham, North Carolina, United States
3 Medicine, Duke University Medical Center, Durham, North Carolina, United States
4 Internal Medicine, University of Utah Medical Center, Salt Lake City, Utah, United States
5 Division of Pulmonary, Critical Care and Occupational (Pulmonary) Medicine, University of Utah, Salt Lake City, Utah, United States
6 Internal Medicine, University of Utah, Salt Lake City, Utah, United States
7 Department of Pediatrics, Division of Pulmonary Diseases, Duke University Medical Center, Durham, North Carolina, United States
* To whom correspondence should be addressed. E-mail: chita001{at}mc.duke.edu.
NAD(P)H oxidase is one of the critical enzymes mediating cellular production of reactive oxygen species and has a central role in airway smooth muscle (ASM) cell proliferation. Since reactive oxygen species also affect ASM contractile response, we hypothesized a regulatory role of NAD(P)H oxidase in ASM contractility. We therefore studied ASM function in wild type mice (C57BL/6J) and mice deficient in a component (p47phox) of NAD(P)H oxidase. In histological sections of the trachea we found that the area occupied by ASM was 17% more in p47phox-/- than in C57BL/6J mice. After correcting for the difference in ASM content, we found that force generation did not vary between the two genotypes. Similarly, their ASM shortening velocity, maximal power, and sensitivity to acetylcholine, as well as airway responsiveness to methacholine in vivo were not significantly different. The main finding of this study was a significantly reduced ASM relaxation in p47phox-/- compared with wild type mice both during the stimulus and after the end of stimulation. The tension relaxation attained at the 20th s of electric field stimulation was respectively 17.6±2.4 and 9.2±2.3% in null and wild type mice (p<0.01 by t-test). Similar significant differences were found in the rate of tension relaxation and the time required to reduce tension by half. Our data suggest that NAD(P)H oxidase may have a role in the structural arrangement and mechanical properties of the airway tissue. Most importantly, we report the first evidence that the p47phox subunit of NAD(P)H oxidase plays a role in ASM relaxation.
