Research Article: Effects of anti-TNF-α in experimental diversion colitis1

Date Published: December 13, 2019

Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em
Cirurgia

Author(s): Ronaldo Parisi Buanaim, José Aires Pereira, Fabio Guilherme Campos, Paulo Gustavo Kotze, Eduardo Felipe Kim Goto, Roberta Laís Silva Mendonça, Danilo Toshio Kanno, Carlos Augusto Real Martinez.

http://doi.org/10.1590/s0102-865020190100000004

Abstract

To evaluate the effects of infliximab on the inflammation of the colonic
mucosa devoid from fecal stream.

Twenty-four rats were submitted to a Hartmann’s procedure. They remained for
12 weeks with the fecal derivation to development of diversion colitis on
excluded colorectal stump. After this period, they were divided into 3
groups: one group received intervention with saline (2.0 mL / week), other
group infliximab at doses of 5 mg/kg/week and the other 10 mg/kg/week for
five consecutively weeks. Concluded the intervention period, the animals
were euthanized to remove colon segments with and without fecal stream.
Colitis was diagnosed by histological analysis and the degree of
inflammation by validated score. The neutrophilic infiltrate was evaluated
by tissue expression of myeloperoxidase identified by immunohistochemical.
The tissue content of myeloperoxidase was measured by computer-assisted
image analysis.

The inflammatory score was high in colonic segments without fecal stream. The
intervention with infliximab reduced the inflammatory score in excluded
colonic segments. The content of myeloperoxidase was reduced in colonic
segments of animals treated with infliximab mainly in high
concentrations.

Intervention with infliximab reduced the inflammation and the neutrophil
infiltrate in colonic segments devoid of the fecal stream.

Partial Text

Diversion colitis (DC) is a benign condition characterized by the appearance of
chronic inflammation in the mucosa of the colon or rectum devoid of the fecal
stream1,2. The etiopathogenic basis for the development of DC is not yet fully
understood3,4. Most of the authors believe that the disease is a nutritional deficiency
syndrome caused by deficiency of the regular supply of short-chain fatty acids
(SCFAs), the main energy substrate for the metabolism of the colonic epithelial
cells5,6. The lack of the regular supply of SCFAs to the cells of the colonic
epithelium causes modifications in energy metabolism increasing the production of
reactive oxygen species (ROS)7. ROS are toxic to cells and their overproduction causes breakage of the
various lines of defense that make up the mucosal barrier, allowing bacteria of the
colon lumen to migrate to the sterile submucosa7–9. In an attempt to combat this bacterial infiltration, neutrophils migrate to
the intestinal vessels, produce large amounts of pro-inflammatory cytokines like
IL-1β, IL-6 and tumor necrosis factor alpha (TNF-a) leading to the damage of the
colonic mucosa characteristic of the disease7.

The accomplishment of this study obeyed Federal Law 6,638 and the guidelines of the
Brazilian College of Animal Experimentation (COBEA). The study was approved by the
Ethics Committee on the Use of Animal in Research of the Universidade São Francisco
(number: 0102262014).

Figure 1 A-C shows colonic segments with fecal
stream of animals submitted to intervention with saline, infliximab 5 mg /kg/ week
and infliximab 10 mg /kg /week, respectively. Figure
1 D-F shows colonic segments without fecal stream of animals submitted to
intervention with saline, infliximab at concentrations of 5 mg/kg/week and 10
mg/kg/week, respectively. In those animals with colonic segments provide of fecal
stream, regardless of the substance used, the mucosal surface is preserved without
formation of ulcers, the colonic glands are intact, and the number of goblet cells
is similar among groups (Fig. 1 A-C). The
colonic segments devoid of fecal stream in animals submitted to intervention with
saline present’s atrophy of the colonic glands, presence of epithelial erosions,
edema with stromal inflammatory infiltrate and reduction in the population of goblet
cells (Fig. 1D). Distinctly, the colonic
segments without fecal stream of the animals submitted to intervention with
infliximab, regardless of the concentration used, the length of colonic glands is
maintained, with decrease of inflammatory infiltrate and increase in numbers of
goblet cells (Fig. 1 E-F).

Studies using different models of chemically induced colitis have shown that there is
an increase in the production of TNF-α in the inflamed colonic mucosa24,27,28. In order to verify if the biological therapy would be able to improve the
induced colitis, some authors evaluated the effectiveness of the application of
anti-TNF-α in these experimental models of colitis25,27,28. The results of these studies showed that the biological therapy with
anti-TNF-α antibodies was effective in improving the inflammatory tissue process and
reducing the tissue levels of TNF-α. In these models of chemically induced colitis,
subcutaneous application of anti-TNF-α at doses of 5 mg/kg/week and 10 mg/kg/week
reduced the inflammatory activity score in the colonic mucosa, TNF-α levels, and
tissue levels of malondialdehyde, an important marker of tissue oxidative stress.
Other authors, with the objective of verifying whether anti-TNF-α use associated
with antioxidants was effective for the treatment of chemically induced colitis by
dextran sulfate, also showed that the use of anti-TNF-α antibodies reduced levels of
TNF-α and improved the inflammatory process of the colonic mucosa29.

The results found in this experimental study show that therapy with infliximab
reduces the inflammation and the neutrophil infiltrate in colonic segments devoid of
the fecal stream. These results allied to the recognized efficacy of infliximab
therapy in the treatment of IBD suggest that the use of the substance in patients
with severe forms of DC is a promising therapeutic strategy that deserves to be
evaluated.

 

Source:

http://doi.org/10.1590/s0102-865020190100000004

 

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