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Crotoxin from Crotalus durissus terrificus is able to down-modulate the acute intestinal inflammation in mice.

Almeida Cde S, Andrade-Oliveira V, Câmara NO, Jacysyn JF, Faquim-Mauro EL - PLoS ONE (2015)

Bottom Line: Crotoxin (CTX) is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect.The CTX administration resulted in decreased weight loss, disease activity index (DAI), macroscopic tissue damage, histopathological score and myeloperoxidase (MPO) activity analyzed after 4 days of acute TNBS colitis.The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3) and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunopathology, Butantan Institute, São Paulo, São Paulo, Brazil.

ABSTRACT
Inflammatory bowel diseases (IBD) is the result of dysregulation of mucosal innate and adaptive immune responses. Factors such as genetic, microbial and environmental are involved in the development of these disorders. Accordingly, animal models that mimic human diseases are tools for the understanding the immunological processes of the IBD as well as to evaluate new therapeutic strategies. Crotoxin (CTX) is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect. Thus, we aimed to evaluate the modulatory effect of CTX in a murine model of colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS). The CTX was administered intraperitoneally 18 hours after the TNBS intrarectal instillation in BALB/c mice. The CTX administration resulted in decreased weight loss, disease activity index (DAI), macroscopic tissue damage, histopathological score and myeloperoxidase (MPO) activity analyzed after 4 days of acute TNBS colitis. Furthermore, the levels of TNF-α, IL-1β and IL-6 were lower in colon tissue homogenates of TNBS-mice that received the CTX when compared with untreated TNBS mice. The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3) and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice. In contrast, increased CD4+FoxP3+ cell population as well as secretion of TGF-β, prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) was observed in TNBS-colitis mice treated with CTX compared with untreated TNBS-colitis mice. In conclusion, the CTX is able to modulate the intestinal acute inflammatory response induced by TNBS, resulting in the improvement of clinical status of the mice. This effect of CTX is complex and involves the suppression of the pro-inflammatory environment elicited by intrarectal instillation of TNBS due to the induction of a local anti-inflammatory profile in mice.

No MeSH data available.


Related in: MedlinePlus

Effect of CTX treatment on the colitis induced by TNBS instillation in BALB/c mice.(A) Body weight changes (%) of BALB/c mice during four days after the intrarectal instillation of TNBS (2.5 mg/animal) in 45% ethanol solution. The control mice received the 45% of ethanol solution. CTX (0.035 mg/kg) was administered i.p. 18 h after TNBS-induced colitis, and saline solution was administered as control. # (p<0.05) ETOH versus TNBS and TNBS+CTX; o (p<0.05) ETOH+CTX versus TNBS and TNBS+CTX; α (p<0.05) TNBS versus TNBS+CTX (n = 4–6 mice/group). (B) Disease activity index calculated as described in material and methods. The results were expressed as mean ± SEM (n = 4–6 mice/group); (C) Macroscopic appearance of colonic portion (4 cm) obtained from each mice/group at 4 days after TNBS-induced colitis; (D) Histological analysis of perirectal segment from mice of distinct experimental groups stained with H&E (Structures: (e) epithelial damage, (i) inflammatory infiltrate and (s) submucosa edema) obtained after 4 days of TNBS-colitis; (E) Histological score of inflammatory reaction perirectal segment of each experimental group of mice (n = 4–5 mice/group); (F) MPO activity of colonic tissue of each experimental mice-group. Groups: ETOH (control- 45% ETOH); ETOH+CTX (45% ethanol group treated with CTX); TNBS (TNBS instillation in 45% ETOH- inflammatory bowel disease) and TNBS+CTX (TNBS-instillation in 45% ETOH that received the CTX) (n = 4–5 animals/group). * p<0.05; *** p<0.001.
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pone.0121427.g001: Effect of CTX treatment on the colitis induced by TNBS instillation in BALB/c mice.(A) Body weight changes (%) of BALB/c mice during four days after the intrarectal instillation of TNBS (2.5 mg/animal) in 45% ethanol solution. The control mice received the 45% of ethanol solution. CTX (0.035 mg/kg) was administered i.p. 18 h after TNBS-induced colitis, and saline solution was administered as control. # (p<0.05) ETOH versus TNBS and TNBS+CTX; o (p<0.05) ETOH+CTX versus TNBS and TNBS+CTX; α (p<0.05) TNBS versus TNBS+CTX (n = 4–6 mice/group). (B) Disease activity index calculated as described in material and methods. The results were expressed as mean ± SEM (n = 4–6 mice/group); (C) Macroscopic appearance of colonic portion (4 cm) obtained from each mice/group at 4 days after TNBS-induced colitis; (D) Histological analysis of perirectal segment from mice of distinct experimental groups stained with H&E (Structures: (e) epithelial damage, (i) inflammatory infiltrate and (s) submucosa edema) obtained after 4 days of TNBS-colitis; (E) Histological score of inflammatory reaction perirectal segment of each experimental group of mice (n = 4–5 mice/group); (F) MPO activity of colonic tissue of each experimental mice-group. Groups: ETOH (control- 45% ETOH); ETOH+CTX (45% ethanol group treated with CTX); TNBS (TNBS instillation in 45% ETOH- inflammatory bowel disease) and TNBS+CTX (TNBS-instillation in 45% ETOH that received the CTX) (n = 4–5 animals/group). * p<0.05; *** p<0.001.

Mentions: To address the modulatory effect of CTX on the intestinal inflammatory process, groups of mice received the intrarectal instillation of TNBS and after 18 h, the toxin was injected i.p. After 4 days of the TNBS-instillation, there was observed a higher percentage of weight loss and clinical score in the TNBS group compared with the control groups (ETOH or ETOH/CTX) (Fig 1A and 1B). A large necrotic area was also verified in the colon of the TNBS group (Fig 1C) confirming the establishment of the experimental colitis in the mice. In contrast, decreased weight loss, clinical score and necrotic area were observed in TNBS mice that received the CTX when compared with the untreated TNBS group (Fig 1A, 1B and 1C).


Crotoxin from Crotalus durissus terrificus is able to down-modulate the acute intestinal inflammation in mice.

Almeida Cde S, Andrade-Oliveira V, Câmara NO, Jacysyn JF, Faquim-Mauro EL - PLoS ONE (2015)

Effect of CTX treatment on the colitis induced by TNBS instillation in BALB/c mice.(A) Body weight changes (%) of BALB/c mice during four days after the intrarectal instillation of TNBS (2.5 mg/animal) in 45% ethanol solution. The control mice received the 45% of ethanol solution. CTX (0.035 mg/kg) was administered i.p. 18 h after TNBS-induced colitis, and saline solution was administered as control. # (p<0.05) ETOH versus TNBS and TNBS+CTX; o (p<0.05) ETOH+CTX versus TNBS and TNBS+CTX; α (p<0.05) TNBS versus TNBS+CTX (n = 4–6 mice/group). (B) Disease activity index calculated as described in material and methods. The results were expressed as mean ± SEM (n = 4–6 mice/group); (C) Macroscopic appearance of colonic portion (4 cm) obtained from each mice/group at 4 days after TNBS-induced colitis; (D) Histological analysis of perirectal segment from mice of distinct experimental groups stained with H&E (Structures: (e) epithelial damage, (i) inflammatory infiltrate and (s) submucosa edema) obtained after 4 days of TNBS-colitis; (E) Histological score of inflammatory reaction perirectal segment of each experimental group of mice (n = 4–5 mice/group); (F) MPO activity of colonic tissue of each experimental mice-group. Groups: ETOH (control- 45% ETOH); ETOH+CTX (45% ethanol group treated with CTX); TNBS (TNBS instillation in 45% ETOH- inflammatory bowel disease) and TNBS+CTX (TNBS-instillation in 45% ETOH that received the CTX) (n = 4–5 animals/group). * p<0.05; *** p<0.001.
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pone.0121427.g001: Effect of CTX treatment on the colitis induced by TNBS instillation in BALB/c mice.(A) Body weight changes (%) of BALB/c mice during four days after the intrarectal instillation of TNBS (2.5 mg/animal) in 45% ethanol solution. The control mice received the 45% of ethanol solution. CTX (0.035 mg/kg) was administered i.p. 18 h after TNBS-induced colitis, and saline solution was administered as control. # (p<0.05) ETOH versus TNBS and TNBS+CTX; o (p<0.05) ETOH+CTX versus TNBS and TNBS+CTX; α (p<0.05) TNBS versus TNBS+CTX (n = 4–6 mice/group). (B) Disease activity index calculated as described in material and methods. The results were expressed as mean ± SEM (n = 4–6 mice/group); (C) Macroscopic appearance of colonic portion (4 cm) obtained from each mice/group at 4 days after TNBS-induced colitis; (D) Histological analysis of perirectal segment from mice of distinct experimental groups stained with H&E (Structures: (e) epithelial damage, (i) inflammatory infiltrate and (s) submucosa edema) obtained after 4 days of TNBS-colitis; (E) Histological score of inflammatory reaction perirectal segment of each experimental group of mice (n = 4–5 mice/group); (F) MPO activity of colonic tissue of each experimental mice-group. Groups: ETOH (control- 45% ETOH); ETOH+CTX (45% ethanol group treated with CTX); TNBS (TNBS instillation in 45% ETOH- inflammatory bowel disease) and TNBS+CTX (TNBS-instillation in 45% ETOH that received the CTX) (n = 4–5 animals/group). * p<0.05; *** p<0.001.
Mentions: To address the modulatory effect of CTX on the intestinal inflammatory process, groups of mice received the intrarectal instillation of TNBS and after 18 h, the toxin was injected i.p. After 4 days of the TNBS-instillation, there was observed a higher percentage of weight loss and clinical score in the TNBS group compared with the control groups (ETOH or ETOH/CTX) (Fig 1A and 1B). A large necrotic area was also verified in the colon of the TNBS group (Fig 1C) confirming the establishment of the experimental colitis in the mice. In contrast, decreased weight loss, clinical score and necrotic area were observed in TNBS mice that received the CTX when compared with the untreated TNBS group (Fig 1A, 1B and 1C).

Bottom Line: Crotoxin (CTX) is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect.The CTX administration resulted in decreased weight loss, disease activity index (DAI), macroscopic tissue damage, histopathological score and myeloperoxidase (MPO) activity analyzed after 4 days of acute TNBS colitis.The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3) and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunopathology, Butantan Institute, São Paulo, São Paulo, Brazil.

ABSTRACT
Inflammatory bowel diseases (IBD) is the result of dysregulation of mucosal innate and adaptive immune responses. Factors such as genetic, microbial and environmental are involved in the development of these disorders. Accordingly, animal models that mimic human diseases are tools for the understanding the immunological processes of the IBD as well as to evaluate new therapeutic strategies. Crotoxin (CTX) is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect. Thus, we aimed to evaluate the modulatory effect of CTX in a murine model of colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS). The CTX was administered intraperitoneally 18 hours after the TNBS intrarectal instillation in BALB/c mice. The CTX administration resulted in decreased weight loss, disease activity index (DAI), macroscopic tissue damage, histopathological score and myeloperoxidase (MPO) activity analyzed after 4 days of acute TNBS colitis. Furthermore, the levels of TNF-α, IL-1β and IL-6 were lower in colon tissue homogenates of TNBS-mice that received the CTX when compared with untreated TNBS mice. The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3) and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice. In contrast, increased CD4+FoxP3+ cell population as well as secretion of TGF-β, prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) was observed in TNBS-colitis mice treated with CTX compared with untreated TNBS-colitis mice. In conclusion, the CTX is able to modulate the intestinal acute inflammatory response induced by TNBS, resulting in the improvement of clinical status of the mice. This effect of CTX is complex and involves the suppression of the pro-inflammatory environment elicited by intrarectal instillation of TNBS due to the induction of a local anti-inflammatory profile in mice.

No MeSH data available.


Related in: MedlinePlus