Bronchial reactivity in male offspring of protein restricted rat dams

Shelley Davis, Elin Thomas, John Holloway, Christopher Torrens. Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK

The maternal environment is now recognised to play a role in the development of cardiometabolic disease in the offspring (Gluckman et al., 2008); however the influence on subsequent respiratory disease is still unclear. The early environment is recognised to be important in the development of asthma (Martino & Prescott, 2011), while low birth weight infants have impaired lung function and increased airway responsiveness (Chan et al, 1988; Lucas et al., 2004). Since a major cause of morbidity and mortality in asthma patients is this hyper-responsive bronchial smooth muscle we investigated bronchial responsiveness in a model of maternal protein restriction.

Pregnant Wistar rats fed either control (C, 18% casein, n = 6) or protein restricted (PR, 9% casein, n = 4) diet from conception to term, before being returned to standard chow immediately postpartum. At 150 days of age, male offspring were sacrificed by cervical dislocation and lung tissue was harvested. At least two segments of bronchi were dissected from the left lobe of the lung and mounted on a wire myograph in Krebs-Henseleit buffer at 37° C. Cumulative concentration-response curves to carbachol (CCh, 0.1 nM – 100 μM), angiotensin II (Ang II, 1 pM – 1 μM) and the thromboxane mimetic U46619 (1 pM – 1 μM) were constructed in all viable segments and changes in isometric tension were recorded. Data are presented as mean ± SEM and differences assessed by Student’s t test. Significance was accepted if p<0.05.

Both CCh and U46619 produced a concentration-dependent constriction of bronchi that were significantly enhanced in the PR group compared to controls (max response: CCh, C, 0.79 ± 0.02 g, n = 6; PR, 1.17 ± 0.03 g, n = 4; p<0.001; U46619: C, 0.60 ± 0.02 g, n = 4; PR, 0.79 ± 0.02 g, n = 4; p<0.001). There was no effect on sensitivity to CCh between the groups (pEC50: C, 6.38 ± 0.20, n = 6, PR, 6.71 ± 0.29, n = 4; p = ns) but a significantly increased sensitivity to U46619 was observed (pEC50: C, 7.60 ± 0.07, n = 4; PR, 8.38 ± 0.04, n = 4; p<0.001). Responses to Ang II were very modest by comparison and did not differ between the groups (max response: C, 0.18 ± 0.09, n = 4; PR, 0.21 ± 0.04, n = 4; p = ns).

This study demonstrates that the bronchi from male offspring of protein restricted dams demonstrate a significantly enhanced contraction to both CCh and thromboxane. These data suggests that poor maternal nutrition may predispose offspring to a phenotype similar to that of asthma.

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Gluckman et al., 2008. N Engl J Med. 359: 61-73.

Lucas et al., 2004 Am J Respir Crit Care Med 170: 534-540

Martino & Prescott 2011, Chest 139, 640-647