DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Intestinal lumen
Bacteria
Antibiotics
Probiotics
Prebiotics
1353
Epithelium
anti-IL-12
IL-12/IL-18
Dendritic
cell
Neutrophil
Lamina
propria
T H 17 cell
Endothelium
Blood vessel lumen
T Reg cell
TGFβ
IL-6
TGFβ
Lymphocyte
T H 0 cell
IFNγ
IL-12
IL-4
T H 2 cell
T H 1 cell
TNFα
Monocyte
IFNγ
TNFα
IFNγ
Macrophage
anti-TNFα
anti-integrin
Figure 47–1. Proposed pathogenesis of inflammatory bowel disease and target sites for pharmacological intervention. Shown are the
interactions among bacterial antigens in the intestinal lumen and immune cells in the intestinal wall. If the epithelial barrier is impaired,
bacterial antigens can gain access to antigen- presenting cells (APC) such as dendritic cells in the lamina propria. These cells then present
the antigen(s) to CD4 + lymphocytes and also secrete cytokines such interleukin (IL)-12 and IL-18, thereby inducing the differentiation
of T H
1 cells in Crohn’s disease (or, under the control of IL-4, type 2 helper T cells [T H
2] in ulcerative colitis). The balance of
pro- inflammatory and anti- inflammatory events is also governed by regulatory T H
17 and T Reg
cells, both of which serve to limit
immune and inflammatory responses in the GI tract. Transforming growth factor (TGF)β and IL-6 are important cytokines that drive
the expansion of the regulatory T cell subsets. The T H
1 cells produce a characteristic array of cytokines, including interferon (IFN)γ
and TNFα, which in turn activate macrophages. Macrophages positively regulate T H
1 cells by secreting additional cytokines, including
IFNγ and TNFα. Recruitment of a variety of leukocytes is mediated by activation of resident immune cells including neutrophils.
Cell adhesion molecules such as integrins are important in the infiltration of leukocytes and novel biological therapeutic strategies
aimed at blocking leukocyte recruitment are effective at reducing inflammation. General immunosuppressants (e.g., glucocorticoids,
thioguanine derivatives, methotrexate, and cyclosporine) affect multiple sites of inflammation. More site-specific intervention involve
intestinal bacteria (antibiotics, prebiotics, and probiotics) and therapy directed at TNFα or IL-12 (see text for further details).
CHAPTER 47
PHARMACOTHERAPY OF INFLAMMATORY BOWEL DISEASE
Although Crohn’s disease and ulcerative colitis share a
number of GI and extraintestinal manifestations and
can respond to a similar array of drugs, emerging evidence
suggests that they result from fundamentally distinct
pathogenetic mechanisms (Xavier and Podolsky,
2007). Histologically, the transmural lesions in Crohn’s
disease exhibit marked infiltration of lymphocytes and
macrophages, granuloma formation, and submucosal
fibrosis, whereas the superficial lesions in ulcerative
colitis have lymphocytic and neutrophilic infiltrates.
Within the diseased bowel in Crohn’s disease, the
cytokine profile includes increased levels of interleukin
(IL)-12, IL-23, interferon- γ, and tumor necrosis factor-α
(TNFα), findings characteristic of T- helper 1 (T H
1)–