Variation in senescent-dependent lung changes in inbred mouse strains

Abstract

Previous studies from our laboratories showed lung development differences between inbred strains of mice. In the present study, the C57BL/6J (B6) and DBA/2J (D2) strains were examined for senescent-dependent differences with respect to the lung structure and function. Specifically, we hypothesize that senescent changes in lung vary between strains due to identifiable gene expression differences. Quasi-static pressure-volume curves and respiratory impedance measurements were performed on 2- and 20-mo-old B6 and D2 mice. Lung volume at 30 cm H(2)O (V(30)) pressure was significantly (P < 0.01) increased with age in both strains, but the increase was proportionally greater in D2 (68%) than in B6 (40%) mice. In addition, decreased elastic recoil pressure at 50% of V(30) and a reduction in airway resistance as a function of positive end-expiratory pressure were observed in 20-mo-old D2 mice but not in B6 mice. Morphometric analysis of lung parenchyma showed significant decreases in elastic fiber content with age in both strains, but the collagen content was significantly (P < 0.01) increased with age in D2 but not B6 mice at 20 mo. Furthermore, using quantitative RT-PCR methods, gene expression differences between strains suggested that D2 mice significantly (P < 0.05) downregulated the expressions of elastin (Eln) and procollagen I, III, and VI (Col1a1, Col3a1, and Col6a3) in lung tissue at 20 mo of age. These age-dependent changes were accompanied by an increased gene expression in matrix metalloproteinase 9 (Mmp9) in D2 and an increase in tissue inhibitor of matrix metalloproteinase (Timp1 and Timp4) in B6 mice. In conclusion, the results from the present study demonstrate that lung mechanics of both strains show significant age-dependent changes. However, changes in D2 mice are accelerated relative to B6 mice. Moreover, gene expression differences appear to be involved in the strain-specific changes of lung mechanic properties.

Tissue elasticity and the ageing elastic fibre

“…Most studies of the ageing lung have failed to identify any change in collagen content (Escolar et al 1997;Lang et al 1994;Pierce and Hocott 1960;Takubo et al 1999;Yamamoto et al 2003), although age-related increases have been observed in both rodent (Goldstein 1982;Huang et al 2007) and human systems (Derrico et al 1989). Similarly, the concentration of elastin and/or elastic fibres in human and rodent lungs has been reported to remain unchanged (Andreotti et al 1983;Takubo et al 1999;Yamamoto et al 2003), to increase (Escolar et al 1994(Escolar et al , 1997Fitzpatrick and Hospelhorn 1962;Pierce and Hocott 1960) and to decrease with age (Derrico et al 1989;Huang et al 2007). There are three potential explanations for the lack of a consensus regarding changes in ECM composition in the ageing lung.…”

“…Third, the respiratory system is exposed to environmental effects such as smoking and air pollutants which are known to influence both lung structure and function (Teramoto et al 1999). Even where attempts have been made to control for these environmental factors using rodent models and to control for differential protein extraction using histological approaches, elastic fibre content in the ageing rat lung may still appear to increase (Escolar et al 1997), decrease (Huang et al 2007) or remain unchanged (Yamamoto et al 2003). As the structural and functional consequences of intrinsic ageing appear to be invariant within mammalian lung, these observations support the hypothesis that age-related changes in the molecular and supramolecular structures of ECM components (John and Thomas 1972), rather than their relative tissue concentrations, underlie gross changes in lung mechanics.…”

Global expression profiles from C57BL/6J and DBA/2J mouse lungs to determine aging-related genes

“…In the latter study (4), D2 mice exhibited a greater susceptibility to severe emphysematous changes following cigarette smoke exposure, which was characterized by more uniform and earlier onset of air space enlargement compared with B6 mice. With respect to basal differences in lung structure and function, B6 and D2 strains display distinguishable phenotypes in lung morphometry, airway resistance, parenchymal elasticity, and ventilatory behavior (23,31,63).The primary goal of the present study was to identify gene expression profile differences between B6 and D2 strains, which serve as genomic indicators of differential aging of the mouse lung (23). A parallel goal of this study was to propose genetic mechanisms regarding the notable age-dependent loss of lung elasticity in D2 mice, which is not seen in B6 mice.…”

“…In the latter study (4), D2 mice exhibited a greater susceptibility to severe emphysematous changes following cigarette smoke exposure, which was characterized by more uniform and earlier onset of air space enlargement compared with B6 mice. With respect to basal differences in lung structure and function, B6 and D2 strains display distinguishable phenotypes in lung morphometry, airway resistance, parenchymal elasticity, and ventilatory behavior (23,31,63).…”

“…The primary goal of the present study was to identify gene expression profile differences between B6 and D2 strains, which serve as genomic indicators of differential aging of the mouse lung (23). A parallel goal of this study was to propose genetic mechanisms regarding the notable age-dependent loss of lung elasticity in D2 mice, which is not seen in B6 mice.…”