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Assessment of murine lung mechanics outcome measures: alignment with those made in asthmatics.

Walker JK, Kraft M, Fisher JT - Front Physiol (2013)

Bottom Line: Murine models of allergic inflammatory airway disease have been widely used to gain mechanistic insight into the pathogenesis of asthma; however, several aspects of murine models could benefit from improvement.A brief description of techniques available to measure murine lung mechanics is provided along with a methodological consideration of their utilization.How murine lung mechanics outcome measures relate to pulmonary physiology measures conducted in humans is discussed and we recommend that, like human studies, outcome measures be standardized for murine models of asthma.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center Durham, NC, USA.

ABSTRACT
Although asthma is characterized as an inflammatory disease, recent reports highlight the importance of pulmonary physiology outcome measures to the clinical assessment of asthma control and risk of asthma exacerbation. Murine models of allergic inflammatory airway disease have been widely used to gain mechanistic insight into the pathogenesis of asthma; however, several aspects of murine models could benefit from improvement. This review focuses on aligning lung mechanics measures made in mice with those made in humans, with an eye toward improving the translational utility of these measures. A brief description of techniques available to measure murine lung mechanics is provided along with a methodological consideration of their utilization. How murine lung mechanics outcome measures relate to pulmonary physiology measures conducted in humans is discussed and we recommend that, like human studies, outcome measures be standardized for murine models of asthma.

No MeSH data available.


Related in: MedlinePlus

Changes in baseline resistance are measureable in mice. Baseline resistance was measured using the forced oscillation technique in anesthetized, paralyzed, tracheotomized mice 24 h after the last OVA challenge (Lin et al., 2012). Duplicate measures of baseline resistance were made in all mice. Animal experiments used to acquire these data were approved by the Duke IACUC. (A) and (B) BALB/C mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2.5 mg alum on days 0 and 14 and challenged by aerosol exposure with 1% OVA for 1 h on days 21, 22, and 23 (Walker et al., 2003). The effect of 60 ug/kg i.v. albuterol on baseline resistance was assessed 1 min after it was administered. (B) C57BL/6J mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2 mg alum on days 1 and 6 and challenged by intranasal insufflation 25 μL OVA (0.2% w/v in saline) containing 2.5 nM of short scrambled peptide. *p < 0.05 from naïve (A) or pre-albuterol (B) as assessed by student's t-test.
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Figure 3: Changes in baseline resistance are measureable in mice. Baseline resistance was measured using the forced oscillation technique in anesthetized, paralyzed, tracheotomized mice 24 h after the last OVA challenge (Lin et al., 2012). Duplicate measures of baseline resistance were made in all mice. Animal experiments used to acquire these data were approved by the Duke IACUC. (A) and (B) BALB/C mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2.5 mg alum on days 0 and 14 and challenged by aerosol exposure with 1% OVA for 1 h on days 21, 22, and 23 (Walker et al., 2003). The effect of 60 ug/kg i.v. albuterol on baseline resistance was assessed 1 min after it was administered. (B) C57BL/6J mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2 mg alum on days 1 and 6 and challenged by intranasal insufflation 25 μL OVA (0.2% w/v in saline) containing 2.5 nM of short scrambled peptide. *p < 0.05 from naïve (A) or pre-albuterol (B) as assessed by student's t-test.

Mentions: The pre-BD FEV1 in humans reflects airway obstruction secondary to airway narrowing. The mouse correlate for determining airway narrowing is baseline airway resistance. In an idealized model, airway resistance mathematically reflects the luminal diameter of the airways (Mitzner, 2007). Murine baseline airway resistance is sufficiently sensitive to allergen treatment that changes can be detected using an acute ovalbumin (OVA) sensitization and challenge model. As shown in Figure 3A, acute OVA treatment increases baseline resistance relative to naïve controls for at least two strains of mouse (C57BL/6J and BALB/C). Comparison of the pre- and post-BD FEV1 in humans indicates the reversibility of airflow obstruction, which reflects the level of airway remodeling. Assessing the reversibility of airway tone can also be accomplished in mice by administration of a β2-AR agonist after initial baseline resistance has been measured. Figure 3B shows a statistically significant decline in baseline resistance immediately following i.v. delivery of 60 ug/kg albuterol in BALB/C mice. Despite receptor expression data suggesting that mice may mediate bronchorelaxation via β1-AR, it was recently shown that the bronchoprotective effect of intravenous (30 ug/kg) albuterol observed in wild type FVB/N mice is absent in β2-AR−/− mutants (Lin et al., 2012). These data provide proof of concept that BD reversibility can be measured in mice. As in humans, measures of baseline resistance and BD reversibility may provide insight into the mechanisms underlying airway narrowing in mice, although correlation of these changes to airway remodeling or airway smooth muscle shortening has yet to be investigated. Additionally, airway remodeling studies necessitate the use of a chronic murine model of asthma, the characteristics and merits of which are reviewed in this issue by Kumar and Foster (Kumar and Foster, 2012).


Assessment of murine lung mechanics outcome measures: alignment with those made in asthmatics.

Walker JK, Kraft M, Fisher JT - Front Physiol (2013)

Changes in baseline resistance are measureable in mice. Baseline resistance was measured using the forced oscillation technique in anesthetized, paralyzed, tracheotomized mice 24 h after the last OVA challenge (Lin et al., 2012). Duplicate measures of baseline resistance were made in all mice. Animal experiments used to acquire these data were approved by the Duke IACUC. (A) and (B) BALB/C mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2.5 mg alum on days 0 and 14 and challenged by aerosol exposure with 1% OVA for 1 h on days 21, 22, and 23 (Walker et al., 2003). The effect of 60 ug/kg i.v. albuterol on baseline resistance was assessed 1 min after it was administered. (B) C57BL/6J mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2 mg alum on days 1 and 6 and challenged by intranasal insufflation 25 μL OVA (0.2% w/v in saline) containing 2.5 nM of short scrambled peptide. *p < 0.05 from naïve (A) or pre-albuterol (B) as assessed by student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569663&req=5

Figure 3: Changes in baseline resistance are measureable in mice. Baseline resistance was measured using the forced oscillation technique in anesthetized, paralyzed, tracheotomized mice 24 h after the last OVA challenge (Lin et al., 2012). Duplicate measures of baseline resistance were made in all mice. Animal experiments used to acquire these data were approved by the Duke IACUC. (A) and (B) BALB/C mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2.5 mg alum on days 0 and 14 and challenged by aerosol exposure with 1% OVA for 1 h on days 21, 22, and 23 (Walker et al., 2003). The effect of 60 ug/kg i.v. albuterol on baseline resistance was assessed 1 min after it was administered. (B) C57BL/6J mice were sensitized by i.p. injection with 10 ug OVA adsorbed to 2 mg alum on days 1 and 6 and challenged by intranasal insufflation 25 μL OVA (0.2% w/v in saline) containing 2.5 nM of short scrambled peptide. *p < 0.05 from naïve (A) or pre-albuterol (B) as assessed by student's t-test.
Mentions: The pre-BD FEV1 in humans reflects airway obstruction secondary to airway narrowing. The mouse correlate for determining airway narrowing is baseline airway resistance. In an idealized model, airway resistance mathematically reflects the luminal diameter of the airways (Mitzner, 2007). Murine baseline airway resistance is sufficiently sensitive to allergen treatment that changes can be detected using an acute ovalbumin (OVA) sensitization and challenge model. As shown in Figure 3A, acute OVA treatment increases baseline resistance relative to naïve controls for at least two strains of mouse (C57BL/6J and BALB/C). Comparison of the pre- and post-BD FEV1 in humans indicates the reversibility of airflow obstruction, which reflects the level of airway remodeling. Assessing the reversibility of airway tone can also be accomplished in mice by administration of a β2-AR agonist after initial baseline resistance has been measured. Figure 3B shows a statistically significant decline in baseline resistance immediately following i.v. delivery of 60 ug/kg albuterol in BALB/C mice. Despite receptor expression data suggesting that mice may mediate bronchorelaxation via β1-AR, it was recently shown that the bronchoprotective effect of intravenous (30 ug/kg) albuterol observed in wild type FVB/N mice is absent in β2-AR−/− mutants (Lin et al., 2012). These data provide proof of concept that BD reversibility can be measured in mice. As in humans, measures of baseline resistance and BD reversibility may provide insight into the mechanisms underlying airway narrowing in mice, although correlation of these changes to airway remodeling or airway smooth muscle shortening has yet to be investigated. Additionally, airway remodeling studies necessitate the use of a chronic murine model of asthma, the characteristics and merits of which are reviewed in this issue by Kumar and Foster (Kumar and Foster, 2012).

Bottom Line: Murine models of allergic inflammatory airway disease have been widely used to gain mechanistic insight into the pathogenesis of asthma; however, several aspects of murine models could benefit from improvement.A brief description of techniques available to measure murine lung mechanics is provided along with a methodological consideration of their utilization.How murine lung mechanics outcome measures relate to pulmonary physiology measures conducted in humans is discussed and we recommend that, like human studies, outcome measures be standardized for murine models of asthma.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center Durham, NC, USA.

ABSTRACT
Although asthma is characterized as an inflammatory disease, recent reports highlight the importance of pulmonary physiology outcome measures to the clinical assessment of asthma control and risk of asthma exacerbation. Murine models of allergic inflammatory airway disease have been widely used to gain mechanistic insight into the pathogenesis of asthma; however, several aspects of murine models could benefit from improvement. This review focuses on aligning lung mechanics measures made in mice with those made in humans, with an eye toward improving the translational utility of these measures. A brief description of techniques available to measure murine lung mechanics is provided along with a methodological consideration of their utilization. How murine lung mechanics outcome measures relate to pulmonary physiology measures conducted in humans is discussed and we recommend that, like human studies, outcome measures be standardized for murine models of asthma.

No MeSH data available.


Related in: MedlinePlus