Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice

Sanctis, George T. De; Merchant, Mark; Beier, David R.; Dredge, Robert; Grobholz, J K; Martin, Thomas R.; Lander, Eric S.; Drazen, Jeffrey M.

doi:10.1038/ng1095-150

Cited by 261 publications

(164 citation statements)

References 31 publications

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“…Of relevance to this report is a mouse quantitative trait locus (QTL) genetic mapping study performed by De Sanctis and colleagues (9). Airway hyperresponsiveness was mapped to mouse chromosome 15 (9) in the same region as the Aqp5 gene locus (12). Two studies have mapped major asthma-susceptibility loci on human chromosome 12q (10,11), the chromosomal location of human Aqp5 gene (12).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Our results show a novel role for AQP5 in airway responsiveness. Interestingly, previously reported genetic linkage studies identify syntenic regions of mouse chromosome 15 (9) and human chromosome 12q (10,11), in which Aqp5 resides (12,13), as containing loci linked with hyperreactivity to bronchoconstriction. This genetic evidence supports the physiological results presented here, which implicate AQP5 in the pathogenesis of bronchial hyperreactivity.…”

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confidence: 99%

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Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation

Krane

Fortner

Hand

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

104

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Although aquaporin 5 (AQP5) is the major water channel expressed in alveolar type I cells in the lung, its actual role in the lung is a matter of considerable speculation. By using immunohistochemical staining, we show that AQP5 expression in mouse lung is not restricted to type I cells, but is also detected in alveolar type II cells, and in tracheal and bronchial epithelium. Aqp5 knockout (Aqp5 ؊/؊ ) mice were used to analyze AQP5 function in pulmonary physiology. Compared with Aqp5 ؉/؉ mice, Aqp5 ؊/؊ mice show a significantly increased concentration-dependent bronchoconstriction to intravenously administered Ach, as shown by an increase in total lung resistance and a decrease in dynamic lung compliance (P < 0.05). Likewise, Penh, a measure of bronchoconstriction, was significantly enhanced in Aqp5 ؊/؊ mice challenged with aerosolized methacholine (P < 0.05). The hyperreactivity to bronchoconstriction observed in the Aqp5 ؊/؊ mice was not due to differences in tracheal smooth muscle contractility in isolated preparations or to altered levels of surfactant protein B. These data suggest a novel pathway by which AQP5 influences bronchoconstriction. This observation is of special interest because studies to identify genetic loci involved in airway hyperresponsiveness associated with asthma bracket genetic intervals on human chromosome 12q and mouse chromosome 15, which contain the Aqp5 gene.A quaporin 5 (AQP5) is a mercury-sensitive water channel expressed in mouse salivary gland acinar cells, alveolar type I cells, lacrimal glands, and the eye (1-3). However, the function of AQP5 in mouse lung physiology and pathophysiology is largely unknown. Recent studies have explored the regulation of Aqp5 gene expression in normal and disease states. In a mouse model of acute lung injury, AQP5 mRNA and protein expression were significantly decreased in association with pulmonary inflammation and edema resulting from adenoviral infection (4). Moreover, AQP5 expression in a murine lung epithelial cell line (MLE-12) is modulated by the proinf lammatory cytokine TNF-␣ through an nuclear factor (NF)-B-dependent pathway (5). Keratinocyte growth factor also has been shown to mediate the differentiation status of alveolar epithelial cells and AQP5 expression (6). However, a clear understanding of AQP5 function in the lung remains to be discerned.Previously published studies have addressed functional questions limited to the examination of the role of AQP5 in type I cells in fluid clearance and airspace-capillary osmotic water permeability. Of significance, isolated perfused lungs from Aqp5 Ϫ/Ϫ mice were shown to have a 10-fold reduction in airspace-capillary osmotic water permeability (7). Experiments addressing the role of AQP5 in alveolar fluid clearance failed to indicate a role for AQP5 in this process under certain physiological conditions (8). Based on the results of these studies, some have concluded that AQP5 does not play a major role in lung physiology. Contrary to these conclusions, the data reported here clearly define a...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation

Krane

Fortner

Hand

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

104

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“…However, a chromosome 15 locus, Bhr2, identified by analysis of bronchial hyperresponsiveness in (A/J Â B6) F 1 Â B6 backcross mice, has been mapped to a region of chromosome 15, close to Tsi3. 28 Potential candidate genes within Tsi3 include Ptk2 (protein tyrosine kinase 2) and Sox10 (SRY-box containing gene 10).…”

Section: Discussionmentioning

confidence: 99%

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Choi

Rose

et al. 2005

Genes Immun

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“…Airway responsiveness was measured as previously described (32,33). In brief, dose-response curves to methacholine were obtained in anesthetized and ventilated mice 24 h after the last aerosol challenge.…”

Section: Determination Of Pulmonary Resistance and Airway Responsivenessmentioning

confidence: 99%

CC Chemokine Receptor-2 Is Not Essential for the Development of Antigen-Induced Pulmonary Eosinophilia and Airway Hyperresponsiveness

MacLean

Sanctis

Ackerman

et al. 2000

The Journal of Immunology

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Monocyte chemoattractant proteins-1 and -5 have been implicated as important mediators of allergic pulmonary inflammation in murine models of asthma. The only identified receptor for these two chemokines to date is the CCR2. To study the role of CCR2 in a murine model of Ag-induced asthma, we compared the pathologic and physiological responses of CCR2−/− mice with those of wild-type (WT) littermates following immunization and challenge with OVA. OVA-immunized/OVA-challenged (OVA/OVA) WT and CCR2−/− mice developed significant increases in total cells recovered by bronchoalveolar lavage (BAL) compared with their respective OVA-immunized/PBS-challenged (OVA/PBS) control groups. There were no significant differences in BAL cell counts and differentials (i.e., macrophages, PMNs, lymphocytes, and eosinophils) between OVA/OVA WT and CCR2−/− mice. Serologic evaluation revealed no significant difference in total IgE and OVA-specific IgE between OVA/OVA WT mice and CCR2−/− mice. Lung mRNA expression and BAL cytokine protein levels of IL-4, IL-5, and IFN-γ were also similar in WT and CCR2−/− mice. Finally, OVA/OVA CCR2−/− mice developed increased airway hyper-responsiveness to a degree similar to that in WT mice. We conclude that following repeated airway challenges with Ag in sensitized mice, the development of Th2 responses (elevated IgE, pulmonary eosinophilia, and lung cytokine levels of IL-4 and IL5) and the development of airway hyper-responsiveness are not diminished by a deficiency in CCR2.

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Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice

Cited by 261 publications

References 31 publications

Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation

Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

CC Chemokine Receptor-2 Is Not Essential for the Development of Antigen-Induced Pulmonary Eosinophilia and Airway Hyperresponsiveness

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