Angiogenesis plays a critical role in metastasis and tumor growth. Human tumors, including colorectal adenocarcinoma, secrete
angiogenic factors, inducing proliferation and chemotaxis of ...microvascular endothelial cells, eventually leading to tumor
neovascularization. The chemokine interleukin 8 (IL-8; CXCL8) exerts potent angiogenic properties on endothelial cells through
interaction with its cognate receptors CXCR1 and CXCR2. As CXCR1 and CXCR2 expression is differentially regulated in tissue-specific
endothelial cells and effects of IL-8 on intestinal endothelial cells are not defined, we characterized the potential IL-8-induced
angiogenic mechanisms in primary cultures of human intestinal microvascular endothelial cells (HIMEC) and IL-8 receptor expression
in human intestinal microvessels. CXCR1 and CXCR2 expression on HIMEC were defined using reverse transcriptase-PCR, immunohistochemistry,
flow cytometry, and Western blot analysis. IL-8-induced downstream signaling events were assessed using immunoblot analysis
and immunofluorescence. The angiogenic effects of IL-8 on HIMEC were determined using proliferation and chemotaxis assays.
HIMEC responded to IL-8 with rapid stress fiber assembly, chemotaxis, enhanced proliferation, and phosphorylation of extracellular
signal-regulated protein kinase 1/2 (ERK 1/2). HIMEC express CXCR2, but not CXCR1. Neutralizing antibodies to CXCR2 diminished
IL-8-induced chemotaxis and stress fiber assembly. Specific inhibitors of ERK 1/2 and phosphoinositide 3-kinase abrogated
endothelial tube formation and IL-8-induced chemotaxis in HIMEC. IL-8 elicits angiogenic responses in microvascular endothelial
cells isolated from human intestine by engaging CXCR2. We confirmed tissue expression of CXCR2 in human intestinal microvessels.
Supported by the notion that malignant colonic epithelial cells overexpress IL-8, CXCR2 blockade may be a novel target for
anti-angiogenic therapy in colorectal adenocarcinoma.
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its ...association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
BACKGROUND AND AIMAlthough an eight-residue insertion in HLA-DQβ1 has been recently identified as a genetic risk factor for idiopathic achalasia, other risk factors are still unknown. In the present ...study, we carried out an epidemiological survey and a genotype–phenotype (G×P) analysis to gain further insights into the etiology of achalasia.
METHODSWe obtained medical data from 696 achalasia patients and 410 controls, as well as their first-degree relatives (2543 of patients and 1497 of controls). For the G×P analysis, we stratified the patients into HLA-DQβ1 insertion carriers and noncarriers.
RESULTSOur data show that patients are more often affected by viral infections before achalasia onset (P<0.0001, most significantly for varicella zoster virus infections). In addition, allergic (P=0.0005) and autoimmune disorders (P=0.0007, most significantly for psoriasis and Sjögren’s syndrome) represent comorbid disease conditions. First-degree relatives of patients also show higher prevalence rates of allergic disorders (P=0.0007) and psoriasis (P=0.016) compared with control relatives. Moreover, the G×P analysis reveals that achalasia is triggered by pregnancies in female HLA-DQβ1 insertion carriers (P=0.031).
CONCLUSIONOur data point to a role of viral infections in the development of achalasia. In addition, they provide evidence for a relationship between achalasia and allergic, as well as autoimmune, disorders. Furthermore, pregnancy seems to be a disease-triggering factor in female HLA-DQβ1 insertion carriers, which points to hormonal and/or immunosuppressive factors influencing disease development.
Background and Aim
Nitric oxide (NO) is an important inhibitory mediator of esophageal function, and its lack leads to typical features of achalasia. In contrast, the role of intramuscular ...interstitial cells of Cajal (ICC‐IM) and vasoactive intestinal peptide (VIP) in lower esophageal sphincter (LES) function is still controversial. Therefore, we examined the function and morphology of the LES in vivo in NO‐deficient (nNOS‐/‐), ICC‐IM‐deficient (W/Wv)‐, and wild‐type (WT) mice.
Methods
Esophageal manometry was performed with a micro‐sized transducer catheter to quantify LES pressure, swallow evoked LES relaxation, and esophageal body motility. The LES morphology was examined by semiquantitative analysis of the immunoreactivity (reduction grade I–IV) of neuronal NOS (nNOS), ICC‐IM, and VIP and their correlation with esophageal function.
Results
nNOS‐/‐ in comparison to WT mice showed a significantly higher LES mean resting pressure with an impaired swallow induced relaxation, whereas W/Wv mice had a hypotensive LES with decreased relaxation. W/Wv and nNOS‐/‐ mice demonstrated differing degrees of tubular esophageal dysfunction.
The reduced immunoreactivity of nNOS correlated with an increased LES pressure and decreased LES relaxation, respectively. Cajal‐cell reduction correlated with impaired LES relaxation, whereas VIP reduction revealed no correlation with esophageal function.
Conclusions
The reduction of ICC‐IM and nNOS can cause dysfunction of the LES and esophageal peristalsis, whereas VIP reduction seems to have no effect. ICC‐IM and nNOS deficiency might be independent relevant causes of esophageal dysfunction similar to that seen in human achalasia.
Thalidomide has been shown to be an effective treatment in various immunologic diseases such as Crohn's disease and rheumatoid arthritis. Its major effect is thought to be mediated by the inhibition ...of TNF-alpha, but the exact mechanism of action is still uncertain. Recent observations could demonstrate that the induction of monocyte apoptosis is a common feature of a variety of anti-inflammatory agents. Therefore, we investigated the role of thalidomide on monocyte apoptosis. Treatment with thalidomide resulted in apoptosis of human peripheral blood monocytes in a time- and dose-dependent manner as demonstrated by annexin V staining. Monocyte apoptosis required the activation of caspases, as combined stimulation by thalidomide together with the broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone markedly prevented monocyte cell death. Apoptosis was triggered by a CD95/CD95 ligand, TNF-RI, and TRAIL-R1 independent pathway with an inhibition of AKT-1 kinase and consecutive mitochondrial release of cytochrome c, followed by the proteolytic activation of initiator caspase-9 and effector caspase-3. Our data suggest that thalidomide-induced monocyte apoptosis is at least partially mediated by a mitochondrial signaling pathway and might contribute to the complex immunomodulatory properties of the drug.
Background: Despite an increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial ...achalasia, its association with well-defined genetic syndromes, the candidate gene approach, and recent presentation of the first systematic genome-wide association study on achalasia suggest the involvement of genetic factors. Methods: In this study we analyzed the frequency with which symptoms associated with esophageal function (swallowing difficulties, regurgitations, retrosternal cramps/pain, heartburn) occur in first-degree relatives of patients with achalasia to determine if screening is useful and justified against the background of early diagnosis in a genetically predisposed population. The survey of data was carried out in 759 relatives of the 359 achalasia patients included in this study by means of structured interviews. Results: Swallowing difficulties as the principal symptom of achalasia were found to occur at least occasionally in 11.2% of first-degree relatives. In comparison with the prevalence of dysphagia in the general population of 7-10% up to 22%, as described in the literature, the frequency of swallowing difficulties does not seem to be increased in our population of relatives. Conclusion: Screening measures do not appear to be justified in spite of the potential genetic background of achalasia.
Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an ...irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQβ1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQβ1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background and Aim
Nitric oxide (
NO
) is an important inhibitory mediator of esophageal function, and its lack leads to typical features of achalasia. In contrast, the role of intramuscular ...interstitial cells of
C
ajal (
ICC‐IM
) and vasoactive intestinal peptide (
VIP
) in lower esophageal sphincter (
LES
) function is still controversial. Therefore, we examined the function and morphology of the
LES
in vivo in
NO
‐deficient (
nNOS
‐/‐
),
ICC‐IM
‐deficient (
W
/
W
v
)‐, and wild‐type (
WT
) mice.
Methods
Esophageal manometry was performed with a micro‐sized transducer catheter to quantify
LES
pressure, swallow evoked
LES
relaxation, and esophageal body motility. The
LES
morphology was examined by semiquantitative analysis of the immunoreactivity (reduction grade
I
–
IV
) of neuronal
NOS
(
nNOS
),
ICC‐IM
, and
VIP
and their correlation with esophageal function.
Results
nNOS
‐/‐
in comparison to
WT
mice showed a significantly higher
LES
mean resting pressure with an impaired swallow induced relaxation, whereas
W
/
W
v
mice had a hypotensive
LES
with decreased relaxation.
W
/
W
v
and
nNOS
‐/‐
mice demonstrated differing degrees of tubular esophageal dysfunction.
The reduced immunoreactivity of
nNOS
correlated with an increased
LES
pressure and decreased
LES
relaxation, respectively.
C
ajal‐cell reduction correlated with impaired
LES
relaxation, whereas
VIP
reduction revealed no correlation with esophageal function.
Conclusions
The reduction of
ICC‐IM
and
nNOS
can cause dysfunction of the
LES
and esophageal peristalsis, whereas
VIP
reduction seems to have no effect.
ICC‐IM
and
nNOS
deficiency might be independent relevant causes of esophageal dysfunction similar to that seen in human achalasia.
Chronic hepatitis C infection still represents a clinical and scientific challenge. Exciting progress has been achieved by the use of combined therapy regimens with pegylated interferon and ribavirin ...resulting in sustained virological response rates of 60-80%, depending on the genotype.
Despite favorable longterm data with regard to viremia, liver histology and serum liver enzymes in treated patients who comply with the criteria of sustained virological response, a complete elimination of the hepatitis C virus (HCV) is rarely observed. Besides liver tissue, peripheral blood mononuclear cells (PBMCs) could be proven as locations of HCV persistence. It is assumed that there are further extrahepatic compartments in the host organism in which virus particles capable of replication remain, in spite of a seemingly successful therapy.
The problem of the existence of small amounts of potentially replicative viruses becomes apparent even in occult hepatitis C, a constellation in which anti-HCV antibodies are missing, but HCV RNA in liver tissue and mostly also in PBMCs exist.
The precise significance of the HCV persistence in the host organism is still inconclusive; according to first research results, however, it can lead to a deterioration of the liver histology. At present, it is also unclear if patients with occult hepatitis C as well as with evidence of HCV RNA in the liver and/or extrahepatic compartments after seemingly successful antiviral treatment are to be regarded as infectious.
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