TY - JOUR
T1 - Non-invasive measurements of exhaled NO and CO associated with methacholine responses in mice
AU - Sethi, Jigme M.
AU - Choi, Augustine M.K.
AU - Calhoun, William J.
AU - Ameredes, Bill T.
N1 - Funding Information:
This study was supported by funding from grants from the NIH (HL-63738 and AI-42365), the American Respiratory Alliance of Western Pennsylvania, and Merck, Inc. All responsibility for the study design, data collection, analysis, and interpretation, as well as the writing and decision to submit the manuscript is due to the authors and not the funding organizations. The authors thank He-Liang Liu, Emeka Ifedigbo, Lauryn Tait, Amber Gligonic, Jesse L. Parks, IV, and Barbara Dixon-McCarthy for their technical assistance with various aspects of these studies. We also thank Dr. Timothy Bil-liar for provision of the NOS-2 and NOS-3 knockout mice, and Dr. Richard A. Flavell for provision of the MKK3 controls, MKK3 and JNK-1 knockout mice utilized in these studies.
PY - 2008/5/27
Y1 - 2008/5/27
N2 - Background: Nitric oxide (NO) and carbon monoxide (CO) in exhaled breath are considered obtainable biomarkers of physiologic mechanisms. Therefore, obtaining their measures simply, non-invasively, and repeatedly, is of interest, and was the purpose of the current study.Methods: Expired NO (ENO) and CO (ECO) were measured non-invasively using a gas micro-analyzer on several strains of mice (C57Bl6, IL-10-/-, A/J, MKK3-/-, JNK1-/-, NOS-2-/- and NOS-3-/-) with and without allergic airway inflammation (AI) induced by ovalbumin systemic sensitization and aerosol challenge, compared using independent-sample t-tests between groups, and repeated measures analysis of variance (ANOVA) within groups over time of inflammation induction. ENO and ECO were also measured in C57Bl6 and IL-10-/- mice, ages 8-58 weeks old, the relationship of which was determined by regression analysis. S-methionyl-L-thiocitrulline (SMTC), and tin protoporphyrin (SnPP) were used to inhibit neuronal/constitutive NOS-1 and heme-oxygenase, respectively, and alter NO and CO production, respectively, as assessed by paired t-tests. Methacholine-associated airway responses (AR) were measured by the enhanced pause method, with comparisons by repeated measures ANOVA and post-hoc testing.Results: ENO was significantly elevated in naïve IL-10-/- (9-14 ppb) and NOS-2-/- (16 ppb) mice as compared to others (average: 5-8 ppb), whereas ECO was significantly higher in naïve A/J, NOS-3-/- (3-4 ppm), and MKK3-/- (4-5 ppm) mice, as compared to others (average: 2.5 ppm). As compared to C57Bl6 mice, AR of IL-10-/-, JNK1-/-, NOS-2-/-, and NOS-3-/- mice were decreased, whereas they were greater for A/J and MKK3-/- mice. SMTC significantly decreased ENO by ~30%, but did not change AR in NOS-2-/- mice. SnPP reduced ECO in C57Bl6 and IL-10-/- mice, and increased AR in NOS-2-/- mice. ENO decreased as a function of age in IL-10-/- mice, remaining unchanged in C57Bl6 mice.Conclusion: These results are consistent with the ideas that: 1) ENO is associated with mouse strain and knockout differences in NO production and AR, 2) alterations of ENO and ECO can be measured non-invasively with induction of allergic AI or inhibition of key gas-producing enzymes, and 3) alterations in AR may be dependent on the relative balance of NO and CO in the airway.
AB - Background: Nitric oxide (NO) and carbon monoxide (CO) in exhaled breath are considered obtainable biomarkers of physiologic mechanisms. Therefore, obtaining their measures simply, non-invasively, and repeatedly, is of interest, and was the purpose of the current study.Methods: Expired NO (ENO) and CO (ECO) were measured non-invasively using a gas micro-analyzer on several strains of mice (C57Bl6, IL-10-/-, A/J, MKK3-/-, JNK1-/-, NOS-2-/- and NOS-3-/-) with and without allergic airway inflammation (AI) induced by ovalbumin systemic sensitization and aerosol challenge, compared using independent-sample t-tests between groups, and repeated measures analysis of variance (ANOVA) within groups over time of inflammation induction. ENO and ECO were also measured in C57Bl6 and IL-10-/- mice, ages 8-58 weeks old, the relationship of which was determined by regression analysis. S-methionyl-L-thiocitrulline (SMTC), and tin protoporphyrin (SnPP) were used to inhibit neuronal/constitutive NOS-1 and heme-oxygenase, respectively, and alter NO and CO production, respectively, as assessed by paired t-tests. Methacholine-associated airway responses (AR) were measured by the enhanced pause method, with comparisons by repeated measures ANOVA and post-hoc testing.Results: ENO was significantly elevated in naïve IL-10-/- (9-14 ppb) and NOS-2-/- (16 ppb) mice as compared to others (average: 5-8 ppb), whereas ECO was significantly higher in naïve A/J, NOS-3-/- (3-4 ppm), and MKK3-/- (4-5 ppm) mice, as compared to others (average: 2.5 ppm). As compared to C57Bl6 mice, AR of IL-10-/-, JNK1-/-, NOS-2-/-, and NOS-3-/- mice were decreased, whereas they were greater for A/J and MKK3-/- mice. SMTC significantly decreased ENO by ~30%, but did not change AR in NOS-2-/- mice. SnPP reduced ECO in C57Bl6 and IL-10-/- mice, and increased AR in NOS-2-/- mice. ENO decreased as a function of age in IL-10-/- mice, remaining unchanged in C57Bl6 mice.Conclusion: These results are consistent with the ideas that: 1) ENO is associated with mouse strain and knockout differences in NO production and AR, 2) alterations of ENO and ECO can be measured non-invasively with induction of allergic AI or inhibition of key gas-producing enzymes, and 3) alterations in AR may be dependent on the relative balance of NO and CO in the airway.
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U2 - 10.1186/1465-9921-9-45
DO - 10.1186/1465-9921-9-45
M3 - Article
C2 - 18505586
AN - SCOPUS:52649094428
SN - 1465-9921
VL - 9
JO - Respiratory Research
JF - Respiratory Research
M1 - 45
ER -