Malcolm C. Roberts

Prostaglandins I2 and E2 have a synergistic role in rescuing epithelial barrier function in porcine ileum.

Prostaglandins (PG) are cytoprotective for gastrointestinal epithelium, possibly because they enhance mucosal repair. The objective of the present studies was to assess the role of prostaglandins in intestinal repair. Intestinal mucosa from porcine ileum subjected to 1 h of ischemia was mounted in Ussing chambers. Recovery of normal transepithelial electrical resistance occurred within 2 h, and continued to increase for a further 2 h to a value twice that of control. The latter response was blocked by inhibition of prostaglandin synthesis, and restored by addition of both carbacyclin (an analog of PGI2) and PGE2, whereas the addition of each alone had little effect. Histologically, prostaglandins had no effect on epithelial restitution or villous contraction, indicating that elevations in transepithelial resistance were associated with increases in paracellular resistance. Furthermore, prostaglandin-stimulated elevations in resistance were inhibited with cytochalasin D, an agent known to stimulate cytoskeletal contraction. Synergistic elevations in transepithelial resistance, similar to those of carbacyclin and PGE2, were also noted after treatment with cAMP and A23187 (a calcium ionophore). We conclude that PGE2 and PGI2 have a synergistic role in restoration of intestinal barrier function by increasing intracellular cAMP and Ca2+, respectively, which in turn signal cytoskeletal-mediated tight junction closure.

Prostaglandin-induced recovery of barrier function in porcine ileum is triggered by chloride secretion

We have previously shown that PGI2 and PGE2 have a synergistic role in restoring electrical transepithelial resistance ( R) in ischemia-injured porcine ileum via the second messengers Ca2+ and cAMP. Because Ca2+ and cAMP stimulate Cl- secretion, we assessed the role of PG-induced Cl-secretion in recovery of R. Mucosa from porcine ileum subjected to ischemia for 45 min was mounted in Ussing chambers and bathed in indomethacin and Ringer solution. Addition of PGs stimulated a twofold increase in R, which was preceded by elevations in short-circuit current (increase of 25 μA/cm2). The PG-induced effect on R was partially inhibited with bumetanide, an inhibitor of Cl- secretion. The remaining elevations in R were similar in magnitude to those induced in ischemic tissues by amiloride, an inhibitor of Na+ absorption. Treatment with 10-4 M 8-bromo-cGMP or 300 mosM mucosal urea resulted in elevations in R similar to those attained with PG treatment. PGs signal recovery of Rvia induction of Cl-secretion and inhibition of Na+absorption, possibly by establishing a transmucosal osmotic gradient.We have previously shown that PGI2 and PGE2 have a synergistic role in restoring electrical transepithelial resistance (R) in ischemia-injured porcine ileum via the second messengers Ca2+ and cAMP. Because Ca2+ and cAMP stimulate Cl- secretion, we assessed the role of PG-induced Cl- secretion in recovery of R. Mucosa from porcine ileum subjected to ischemia for 45 min was mounted in Ussing chambers and bathed in indomethacin and Ringer solution. Addition of PGs stimulated a twofold increase in R, which was preceded by elevations in short-circuit current (increase of 25 microA/cm2). The PG-induced effect on R was partially inhibited with bumetanide, an inhibitor of Cl- secretion. The remaining elevations in R were similar in magnitude to those induced in ischemic tissues by amiloride, an inhibitor of Na+ absorption. Treatment with 10(-4) M 8-bromo-cGMP or 300 mosM mucosal urea resulted in elevations in R similar to those attained with PG treatment. PGs signal recovery of R via induction of Cl- secretion and inhibition of Na+ absorption, possibly by establishing a transmucosal osmotic gradient.

Constipation, laxative use, and colon cancer in a North Carolina population.

OBJECTIVE:The aim of this study was to determine whether bowel movement frequency and laxative use and type were associated with risk of colon cancer in white and black men and women.METHODS:We conducted a population-based, case–control study with equal representation by blacks. Eligible subjects between ages 40 and 80 yr residing in urban and rural communities in North Carolina were asked about bowel habits and laxatives during face-to-face interviews. There were 643 cases (349 white, 294 black) and 1048 controls (611 white, 437 black).RESULTS:Constipation, defined as fewer than three reported bowel movements per wk, was associated with a greater than two-fold risk of colon cancer (OR 2.36; 95% CI = 1.41–3.93) adjusted for age, race, sex, and relevant confounders. The association was greater for women (OR 2.69; 95% CI = 1.46–4.94) than for men (OR 1.73; 95% CI = 0.61–4.88) and stronger in blacks than whites. Black women had the highest risk (OR 3.42; 95% CI = 1.60–7.34), which remained significant (OR 3.21; 95% CI = 1.46–7.04) even after excluding subjects with late stage (distant) disease. The OR for constipation was slightly higher for distal than for proximal colon cancers. There was no association with laxative use (OR 0.88; 95% CI = 0.69–1.11). Fiber commercial laxatives appeared to exert a protective effect in a small subgroup.CONCLUSIONS:This study provides support for a positive association between constipation and increased risk for colon cancer. Women, especially black women with constipation, seem to be at the highest risk.

Glutamine and transforming growth factor-α stimulate extracellular regulated kinases and enhance recovery of villous surface area in porcine ischemic-injured intestine ☆ ☆☆

BACKGROUND Epidermal growth factor (EGF) signals enterocyte proliferation via extracellular regulated kinases (ERKs). Because glutamine is required for EGF-stimulated proliferation and stimulates ERKs in intestinal cell culture, we hypothesized that glutamine and the EGF-related peptide transforming growth factor-alpha (TGF-alpha) would synergistically enhance repair associated with stimulation of ERKs. METHODS Thiry-Vella loops were created in juvenile pigs. One half of the loop was subjected to 2 hours of ischemia, and the other half served as control. Loops were infused daily with Ringers solution containing 140 mmol/L glucose, 140 mmol/L glutamine, 140 mmol/L glucose plus 60 micrograms/L TGF-alpha, or 140 mmol/L glutamine plus 60 micrograms/L TGF-alpha. RESULTS After 2 hours of ischemia, complete villous epithelial sloughing was present. By 18 hours, villous epithelium had fully restituted, but villi remained stunted until 144 hours after injury. Glutamine + TGF-alpha triggered sustained increases in ERK activity compared with glucose-treated tissues (maximal at 18 hours), whereas glutamine alone or glucose + TGF-alpha caused only transient elevations in ERK activity. By 72 hours, villous surface area had increased to normal values with glutamine plus TGF-alpha treatment, whereas villi remained stunted with glucose alone, glutamine alone, or glucose plus TGF-alpha. CONCLUSIONS Glutamine plus TGF-alpha treatment restored mucosal architecture within 72 hours of severe ischemic injury associated with sustained elevations in ERK activity.

Is reperfusion injury an important cause of mucosal damage after porcine intestinal ischemia

BACKGROUND Intestinal ischemic injury is exacerbated by reperfusion in rodent and feline models because of xanthine oxidase-initiated reactive oxygen metabolite formation and neutrophil infiltration. Studies were conducted to determine the relevance of reperfusion injury in the juvenile pig, whose low levels of xanthine oxidase are similar to those of the human being. METHODS Ischemia was induced by means of complete mesenteric arterial occlusion, volvulus, or hemorrhagic shock. Injury was assessed by means of histologic examination and measurement of lipid peroxidation. In addition, myeloperoxidase, as a marker of neutrophil infiltration, and xanthine oxidase-xanthine dehydrogenase were measured. RESULTS Significant ischemic injury was evident after 0.5 to 3 hours of complete mesenteric occlusion or 2 hours of shock or volvulus. In none of these models was the ischemic injury worsened by reperfusion. To maximize superoxide production, pigs were ventilated on 100% O2, but only limited reperfusion injury (1.2-fold increase in histologic grade) was noted. Xanthine oxidase-xanthine dehydrogenase levels were negligible (0.4 +/- 0.4 mU/gm). CONCLUSIONS Reperfusion injury may not play an important role in intestinal injury under conditions of complete mesenteric ischemia and low-flow states in the pig. This may result from low xanthine oxidase-xanthine dehydrogenase levels, which are similar to those found in the human being.