Abstract
The aging-associated cellular and molecular changes in esophagus have not been established, yet. Thus we evaluated histological structure, interstitial cells of Cajal (ICCs), neuronal nitric oxide synthase (nNOS)-positive cells, and contractility in the esophagus of Fischer 344 rat at different ages (6-, 31-, 74-weeks, and 2-years). The lamina propria thickness and endomysial area were calculated. The immunoreactivity of c-Kit, nNOS and protein gene product (PGP) 9.5 was counted after immunohistochemistry. Expression of c-Kit, stem cell factor (SCF), nNOS and PGP 9.5 mRNA was measured by real-time PCR, and expression of c-Kit and nNOS protein was detected by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The lamina propria thickness increased (6 week vs 2 year, P = 0.005) and the endomysial area of longitudinal muscle decreased with aging (6 week vs 2 year, P<0.001), while endomysial area of circular muscle did not significantly decrease. The proportions of NOS-immunoreactive cells and c-Kit-immunoreactive areas declined with aging (6 week vs 2 year; P<0.001 and P = 0.004, respectively), but there was no significant change of PGP 9.5-immunopositiviy. The expressions of nNOS, c-Kit and SCF mRNA also reduced with aging (6 week vs 2 year; P = 0.006, P = 0.001 and P = 0.006, respectively), while the change of PGP 9.5 mRNA expression was not significant. Western blot showed the significant decreases of nNOS and c-Kit protein expression with aging (6 week vs 2 year; P = 0.008 and P = 0.012, respectively). The EFS-induced esophageal contractions significantly decreased in 2-yr-old rat compared with 6-wk-old rats, however, L-NG-Nitroarginine methylester did not significantly increase the spontaneous and EFS-induced contractions in the 6-wk- and 2-yr-old rat esophagus. In conclusion, an increase of lamina propria thickness, a decrease of endomysial area, c-Kit, SCF and NOS expression with preserved total enteric neurons, and contractility in aged rat esophagus may explain the aging-associated esophageal dysmotility.
Highlights
Aging affects the structure and function of gut as a result of accumulation of diverse deleterious cellular and biochemical changes [1]
A recent human research showed decreased upper esophageal sphincter pressure, distal esophageal motility and peristaltic velocity with advancing age using high resolution esophageal manometry [5]. These changes may be a major contributor to dysphagia and reflux symptom which are commonly reported in elderly individuals [6, 7]
The average thickness of lamina propria in the 74-wk and 2-yr-old rats significantly increased compared with 6- and 31-wk-old rats (6-wk vs 74-wk, P = 0.005; 6-wk vs 2-yr, P = 0.005; 31-wk vs 74-wk, P = 0.029; 31-wk vs 2-yr, P = 0.03) (Table 1 and Fig 2A)
Summary
Aging affects the structure and function of gut as a result of accumulation of diverse deleterious cellular and biochemical changes [1]. Several human studies reported aging-associated changes in the esophageal motility such as increased esophageal stiffness, reduced peristaltic function [2] and decreased lower esophageal sphincter (LES) relaxation [3, 4]. A recent human research showed decreased upper esophageal sphincter pressure, distal esophageal motility and peristaltic velocity with advancing age using high resolution esophageal manometry [5]. These changes may be a major contributor to dysphagia and reflux symptom which are commonly reported in elderly individuals [6, 7]. The extent of enteric neuronal loss during aging is likely to be variable in different studies. Swollen and dystrophic nerve fibers have been described in the aging rat [15] and mouse [17]
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