Role of Tenascin-X in regulating TGF-ß/Smad signaling pathway in pathogenesis of slow transit constipation.

BACKGROUND: Chronic constipation is a gastrointestinal functional disease that seriously harms physical and mental health and impacts the quality of life of patients. Its incidence rate is 2%-27%. Slow transit constipation (STC) is a common type of chronic functional constipation, accounting for 10.3%-45.5% of such cases. Scholars have performed many studies on the pathogenesis of STC. These studies have indicated that the occurrence of STC may be related to multiple factors, such as dysfunction of the enteric nervous system, interstitial cells of Cajal (ICC) damage, and changes in neurotransmitters regulating intestinal peristalsis. AIM: To investigate the role of Tenascin-X (TNX) in regulating the TGF-ß/Smad signaling pathway in the pathogenesis of STC. METHODS: This study included an experimental group and a control group. The experimental group included 28 patients with severe colonic STC, and the control group included 18 patients with normal colon tissues. Immunohistochemistry (IHC) was used to detect c-Kit, a specific marker of the ICC. Western blot, immunofluorescence, and IHC were used to detect the localization and expression of TNX and TGF-ß/Smad. RESULTS: IHC showed that the number of ICC with positive c-Kit expression was significantly reduced in the colon of STC patients (22.17 ± 3.28 vs 28.69 ± 3.53, P < 0.05) and that the distribution was abnormal. Western blot results showed that c-Kit and Smad7 levels were significantly decreased in the colon of STC patients (c-kit: 0.462 ± 0.099 vs 0.783 ± 0.178, P < 0.01; Smad7: 0.626 ± 0.058 vs 0.799 ± 0.03, P < 0.01) and that TNX and Smad2/3 levels were higher in the STC group (TNX: 0.868 ± 0.028 vs 0.482 ± 0.032, P < 0.01). There was no significant difference in TGF-ß between the two groups (0.476 ± 0.028 vs 0.511 ± 0.044, P = 0.272). Pearson correlation analysis showed that the TNX protein exhibited a strong correlation with Smad2/3 and Smad7 (P < 0.05, |R| > 0.8) and TGF-ß (P < 0.05, |R| = 0.7). CONCLUSION: The extracellular matrix protein TNX may activate the TGF-ß/Smad signaling pathway by upregulating the Smad 2/3 signaling protein and thereby induce slight or complete epithelial stromal cell transformation, leading to an abnormal distribution and dysfunction of ICC in the diseased colon, which promotes the occurrence and development of STC.

Surgical outcomes of subtotal colectomy with antiperistaltic caecorectal anastomosis vs total colectomy with ileorectal anastomosis for intractable slow-transit constipation.

BACKGROUND: Few studies have compared the surgical outcomes of different surgical procedures currently used to treat refractory colonic slow-transit constipation (STC), despite the increase in the number of cases. This study aimed to analyse the long-term surgical outcomes of subtotal colectomy with antiperistaltic caecorectal anastomosis (SC-ACRA) vs total colectomy with ileorectal anastomosis (TC-IRA) for severe STC. METHODS: Between January 2005 and January 2015, we retrospectively collected clinical data of 55 patients who underwent TC-IRA (n = 35) or SC-ACRA (n = 20) for severe STC at our institution. The post-operative functional outcomes between the two groups were compared. RESULTS: There were no significant differences in age (P = 0.655), sex (P = 0.234), period of constipation (P = 0.105) and defecation frequency (P = 0.698) between the TC-IRA and SC-ACRA groups. During a median follow-up period of 72 months (range, 12-120 months), there were no significant differences between the TC-IRA and SC-ACRA groups regarding the median number of bowel movements per day [3 (1/6-7) vs 3 (1/6-5), P = 0.578], Cleveland Clinic Florida Constipation Score [2 (0-20) vs 2 (0-19), P = 0.454], Cleveland Clinic Incontinence Score [0 (0-5) vs 0 (0-2), P = 0.333] and Gastrointestinal Quality of Life Index [122 (81-132) vs 120 (80-132), P = 0.661]. Moreover, there was no significant difference in the incidence of post-operative complications between the two groups (37.1% vs 25.0%, P = 0.285). CONCLUSIONS: Our findings indicate that both TC-IRA and SC-ACRA are effective treatments for severe STC, with similar long-term outcomes.

Lumican expression in diaphragm induced by mechanical ventilation.

BACKGROUND: Diaphragmatic dysfunction found in the patients with acute lung injury required prolonged mechanical ventilation. Mechanical ventilation can induce production of inflammatory cytokines and excess deposition of extracellular matrix proteins via up-regulation of transforming growth factor (TGF)-ß1. Lumican is known to participate in TGF-ß1 signaling during wound healing. The mechanisms regulating interactions between mechanical ventilation and diaphragmatic injury are unclear. We hypothesized that diaphragmatic damage by short duration of mechanical stretch caused up-regulation of lumican that modulated TGF-ß1 signaling. METHODS: Male C57BL/6 mice, either wild-type or lumican-null, aged 3 months, weighing between 25 and 30 g, were exposed to normal tidal volume (10 ml/kg) or high tidal volume (30 ml/kg) mechanical ventilation with room air for 2 to 8 hours. Nonventilated mice served as control groups. RESULTS: High tidal volume mechanical ventilation induced interfibrillar disassembly of diaphragmatic collagen fiber, lumican activation, type I and III procollagen, fibronectin, and α-smooth muscle actin (α-SMA) mRNA, production of free radical and TGF-ß1 protein, and positive staining of lumican in diaphragmatic fiber. Mechanical ventilation of lumican deficient mice attenuated diaphragmatic injury, type I and III procollagen, fibronectin, and α-SMA mRNA, and production of free radical and TGF-ß1 protein. No significant diaphragmatic injury was found in mice subjected to normal tidal volume mechanical ventilation. CONCLUSION: Our data showed that high tidal volume mechanical ventilation induced TGF-ß1 production, TGF-ß1-inducible genes, e.g., collagen, and diaphragmatic dysfunction through activation of the lumican.