Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery

Hagiwara, Chikara; Tanaka, Masanori; Kudo, Hiroto

doi:10.1046/j.1440-1746.2002.02791.x

Cited by 114 publications

(79 citation statements)

References 39 publications

(36 reference statements)

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“…These results indicate that SP-mediated Akt phosphorylation may play an important role in mucosal healing during recovery from colitis. As well, our findings further associate SP with the pathophysiology of IBD because increased apoptosis and oxidative stress are evident in the colon of patients with ulcerative colitis and Crohn's disease (33)(34)(35).…”

Section: Discussionsupporting

confidence: 73%

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

Koon

Zhao

Zhan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

100

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We examined the hypothesis that substance P (SP) and the neurokinin-1 receptor (NK-1R), both in vitro and in vivo, promote mucosal healing during recovery from colitis by stimulating antiapoptotic pathways in human colonic epithelial cells. For the in vitro experiments, human nontransformed NCM460 colonocytes stably transfected with NK-1R (NCM460-NK-1R cells) were exposed to SP, and cell viability assays, TUNEL assays, and Western blot analyses were used to detect apoptotic and antiapoptotic pathways. SP exposure of NCM460-NK-1R colonocytes stimulated phosphorylation of the antiapoptotic molecule Akt and inhibited tamoxifeninduced cell death and apoptosis evaluated by the cell viability assay and poly(ADP-ribose) polymerase cleavage, respectively. SP-induced phosphorylation of Akt and cleavage of poly(ADPribose) polymerase were inhibited by blockade of integrin ␣V␤3, Jak2, and activation of phosphatidylinositol 3-kinase. For the in vivo experiments, C57BL/6 mice, administered 5% dextran sulfate (DSS) dissolved in tap water for 5 days followed by a 5-day recovery period, were treated with the NK-1R antagonist CJ-12,255 or vehicle. Vehicle-treated mice showed increased colonic Akt phosphorylation and apoptosis compared with mice that received no DSS. In contrast, daily i.p. administration of CJ-12,255 for 5 days post-DSS suppressed Akt activation, exacerbated colitis, and enhanced apoptosis, and pharmacologic inhibition of Akt, either alone or together with CJ-12,255, produced a similar effect. Thus, SP, through NK-1R, possesses antiapoptotic effects in the colonic mucosa by activating Akt, which prevents apoptosis and mediates tissue recovery during colitis.apoptosis ͉ colitis

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Section: Discussionsupporting

confidence: 73%

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

Koon

Zhao

Zhan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

100

View full text Add to dashboard Cite

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“…Increased permeability of the epithelial barrier and increased apoptotic rates of epithelial cells have been implicated to be major factors in the pathogenesis of intestinal inflammation (25,64). Our observation that cecal inflammation is more pronounced in Akt2 KO mice during Salmonella infection may be associated with the lack of the antiapoptotic molecule Akt2.…”

Section: Discussionmentioning

confidence: 59%

Protective Role of Akt2 in Salmonella enterica Serovar Typhimurium-Induced Gastroenterocolitis

Kum

2011

Infect Immun

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The Salmonella effector protein SopB has previously been shown to induce activation of Akt and protect epithelial cells from apoptosis in vitro. To characterize the role of Akt2 in host defense against Salmonella enterica serovar Typhimurium infection, wild-type (WT) mice and mice lacking Akt2 (Akt2 knockout [KO] mice) were infected using a Salmonella acute gastroenteritis model. Infected Akt2 KO mice showed a more pronounced morbidity and mortality associated with higher bacterial loads in the intestines and elevated levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), and MCP-1, in the colons at 1 day postinfection compared to those shown in WT mice. Histopathological assessment and immunohistochemical analysis of cecal sections at 1 day postinfection revealed more severe inflammation and higher levels of neutrophil infiltration in the ceca of Akt2 KO mice. Flow cytometry analysis further confirmed an increase in the recruitment of Gr-1 ؉ CD11b ؉ neutrophils and F4/80 ؉ CD11b ؉ macrophages in the intestines of infected Akt2 KO mice. Additionally, enhanced levels of annexin V ؉ and terminal transferase dUTP nick end labeling-positive (TUNEL ؉ ) apoptotic cells in the intestines of infected Akt2 KO mice were also observed, indicating that Akt2 plays an essential role in protection against apoptosis. Finally, the differences in bacterial loads and cecal inflammation in WT and Akt2 KO mice infected with WT Salmonella were abolished when these mice were infected with the sopB deletion mutant, indicating that SopB may play a role in protecting the mice from Salmonella infection through the activation of Akt2. These data demonstrate a definitive phenotypic abnormality in the innate response in mice lacking Akt2, underscoring the important protective role of Akt2 in Salmonella infection.

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“…TUNEL-positive nuclei were clearly identified as brown-stained nuclei, indicating the presence of DNA fragmentation due to apoptosis. TUNEL-positive staining correlated with morphological features of apoptosis (nuclear and cytoplasmic blebbing, chromatin margination) (1,38,43). The apoptotic index was quantified as the number of apoptotic nuclei per crypt, that is:…”

Section: Assessment Of Apoptosismentioning

confidence: 99%

“…The areas of mucosal ulceration seen on gross exam of UC specimens demonstrate markedly increased epithelial cell apoptosis and necrosis on histologic examination, both in human UC (1) as well as in animal models of this disease (2,3). Importantly, the epithelial cell apoptotic rate correlates with the severity of the disease (1). Although the pathophysiology of UC is believed to be multifactorial, the cytokine tumor necrosis factor-alpha (TNF-α) has been implicated as a critical inflammatory mediator in UC (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

et al. 2007

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Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor alpha (TNF-α). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-α expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-α, Bcl-2, and Bax expression. TNF-α mRNA was significantly lower with ACE-I treatment compared to placebo at every time point; as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.

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Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery

Abstract: The results suggest that epithelial apoptosis is a non-specific phenomenon and that an increased number of apoptotic cells exceeding histiocyte phagocytic capacity may play a part in the disruption of epithelial defenses and further accelerate mucosal inflammation.

Cited by 114 publications

References 39 publications

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

Protective Role of Akt2 in Salmonella enterica Serovar Typhimurium-Induced Gastroenterocolitis

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

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