Genetically determined heterogeneity of lung disease in a mouse model of airway mucus obstruction

Livraghi-Butrico, Alessandra; Grubb, Barbara R; Kelly, Elizabeth J.; Wilkinson, Kristen J.; Yang, Huifang; Geiser, Marianne; Randell, Scott H.; Boucher, Richard C.; O'Neal, Wanda K. (2012). Genetically determined heterogeneity of lung disease in a mouse model of airway mucus obstruction. Physiological genomics, 44(8), pp. 470-484. American Physiological Society 10.1152/physiolgenomics.00185.2011

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Mucus clearance is an important airway innate defense mechanism. Airway-targeted overexpression of the epithelial Na(+) channel β-subunit [encoded by sodium channel nonvoltage gated 1, beta subunit (Scnn1b)] in mice [Scnn1b-transgenic (Tg) mice] increases transepithelial Na(+) absorption and dehydrates the airway surface, which produces key features of human obstructive lung diseases, including mucus obstruction, inflammation, and air-space enlargement. Because the first Scnn1b-Tg mice were generated on a mixed background, the impact of genetic background on disease phenotype in Scnn1b-Tg mice is unknown. To explore this issue, congenic Scnn1b-Tg mice strains were generated on C57BL/6N, C3H/HeN, BALB/cJ, and FVB/NJ backgrounds. All strains exhibited a two- to threefold increase in tracheal epithelial Na(+) absorption, and all developed airway mucus obstruction, inflammation, and air-space enlargement. However, there were striking differences in neonatal survival, ranging from 5 to 80% (FVB/NJ<BALB/cJ<C3H/HeN<C57BL/6N), which correlated with the incidence of upper airway mucus plugging and the levels of Muc5b in bronchoalveolar lavage. The strains also exhibited variable Clara cell necrotic degeneration in neonatal intrapulmonary airways and a variable incidence of pulmonary hemorrhage and lung atelectasis. The spontaneous occurrence of a high surviving BALB/cJ line, which exhibited delayed onset of Na(+) hyperabsorption, provided evidence that: 1) air-space enlargement and postnatal death were only present when Na(+) hyperabsorption occurred early, and 2) inflammation and mucus obstruction developed whenever Na(+) hyperabsorption was expressed. In summary, the genetic context and timing of airway innate immune dysfunction critically determines lung disease phenotype. These mouse strains may be useful to identify key modifier genes and pathways.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Cell Biology
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Yang, Huifang and Geiser, Marianne

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1094-8341

Publisher:

American Physiological Society

Language:

English

Submitter:

Marianne Geiser Kamber

Date Deposited:

27 Jun 2014 09:25

Last Modified:

27 Jun 2014 09:25

Publisher DOI:

10.1152/physiolgenomics.00185.2011

PubMed ID:

22395316

URI:

https://boris.unibe.ch/id/eprint/47801

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