Are interstitial cells of Cajal involved in mechanical stress-induced gene expression and impairment of smooth muscle contractility in bowel obstruction?

Background And Aims: The network of interstitial cells of Cajal (ICC) is altered in obstructive bowel disorders (OBD). However, whether alteration in ICC network is a cause or consequence of OBD remains unknown. This study tested the hypothesis that mechanical dilation in obstruction disrupts the ICC network and that ICC do not mediate mechanotranscription of COX-2 and impairment of smooth muscle contractility in obstruction.

Methods: Medical-grade silicon bands were wrapped around the distal colon to induce partial obstruction in wild-type and ICC deficient (W/W(v)) mice.

Results: In wild-type mice, colon obstruction led to time-dependent alterations of the ICC network in the proximal colon segment. Although unaffected on days 1 and 3, the ICC density decreased markedly and the network was disrupted on day 7 of obstruction. COX-2 expression increased, and circular muscle contractility decreased significantly in the segment proximal to obstruction. In W/W(v) control mice, COX-2 mRNA level was 4.0 (±1.1)-fold higher (n=4) and circular muscle contractility was lower than in wild-type control mice. Obstruction further increased COX-2 mRNA level in W/W(v) mice to 7.2 (±1.0)-fold vs. W/W(v) controls [28.8 (±4.1)-fold vs. wild-type controls] on day 3. Obstruction further suppressed smooth muscle contractility in W/W(v) mice. However, daily administration of COX-2 inhibitor NS-398 significantly improved muscle contractility in both W/W(v) sham and obstruction mice.

Conclusions: Lumen dilation disrupts the ICC network. ICC deficiency has limited effect on stretch-induced expression of COX-2 and suppression of smooth muscle contractility in obstruction. Rather, stretch-induced COX-2 plays a critical role in motility dysfunction in partial colon obstruction.