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EBioMedicine Mar 2019Gut integrity is compromised in abdominal sepsis with increased cellular apoptosis and altered barrier permeability. Intestinal epithelial cells (IEC) form a...
BACKGROUND
Gut integrity is compromised in abdominal sepsis with increased cellular apoptosis and altered barrier permeability. Intestinal epithelial cells (IEC) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is strongly involved in the mucosal inflammatory response and immune response. Recent research indicates the involvement of the stimulator of interferons genes (STING) pathway in uncontrolled inflammation and gut mucosal immune response.
METHODS
We investigated the role of STING signaling in sepsis and intestinal barrier function using intestinal biopsies from human patients with abdominal sepsis and with an established model of abdominal sepsis in mice.
FINDINGS
In human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls, and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Moreover, elevated STING expression was associated with high levels of serum intestinal fatty acid binding protein that served as a marker of enterocyte damage. In mice, the intestinal STING signaling pathway was markedly activated following the induction of sepsis induced by cecal ligation perforation (CLP). STING knockout mice showed an alleviated inflammatory response, attenuated gut permeability, and decreased bacterial translocation. Whereas mice treated with a STING agonist (DMXAA) following CLP developed greater intestinal apoptosis and a more severe systemic inflammatory response. We demonstrated that mitochondrial DNA (mtDNA) was released during sepsis, inducing the intestinal inflammatory response through activating the STING pathway. We finally investigated DNase I administration at 5 hours post CLP surgery, showing that it reduced systemic mtDNA and inflammatory cytokines levels, organ damage, and bacterial translocation, suggesting that inhibition of mtDNA-STING signaling pathway protects against CLP-induced intestinal barrier dysfunction.
INTERPRETATION
Our results indicate that the STING signaling pathway can contribute to lethal sepsis by promoting IEC apoptosis and through disrupting the intestinal barrier. Our findings suggest that regulation of the mtDNA-STING pathway may be a promising therapeutic strategy to promote mucosal healing and protect the intestinal barrier in septic patients. FUND: National Natural Science Foundation of China.
Topics: Animals; Apoptosis; Bacteria; Cytokines; DNA, Mitochondrial; Dendritic Cells; Disease Models, Animal; Epithelial Cells; Humans; Interferon Regulatory Factor-3; Intestinal Mucosa; Intestines; Leukocytes, Mononuclear; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Sepsis; Xanthones
PubMed: 30878597
DOI: 10.1016/j.ebiom.2019.02.055 -
Frontiers in Allergy 2021Itch is a nociceptive sensation linked with reflexes and cognitive motor actions. We traditionally think of itch as a sensation of the skin related to allergy, an insect... (Review)
Review
Itch is a nociceptive sensation linked with reflexes and cognitive motor actions. We traditionally think of itch as a sensation of the skin related to allergy, an insect sting or interestingly, anxiety and frustration. Less understood and considered are the physiological processes involved in the itching sensation that occurs at mucosal and junctional dermal sites, which is extraordinary as from an evolutionary point of view these sites serve important guardian roles, rich in sensory nerves and inflammatory cells. Despite itch being an ancient reflex and evolutionarily conserved phenomenon, better clinical understanding of the nuances between sites of itch sensation may lead to improved clinical outcomes. This review invites readers to appreciate itch beyond the skin by highlighting several specific itch patterns-nasal, oral, auricular, vulvovaginal, anal, and perineal itch-the pathophysiological mechanisms that underlie them, the clinical patterns these may cause, and some unique treatments.
PubMed: 35386995
DOI: 10.3389/falgy.2021.700368 -
Oncotarget Feb 2018Anorectal melanoma is an uncommon and aggressive mucosal melanocytic malignancy. Due to its rarity, the pre-operative diagnosis remains difficult. The first symptoms are... (Review)
Review
Anorectal melanoma is an uncommon and aggressive mucosal melanocytic malignancy. Due to its rarity, the pre-operative diagnosis remains difficult. The first symptoms are non-specific such as anal bleeding, anal mass or pain. Although anorectal melanoma carries a poor prognosis; optimal therapeutics strategies are unclear. Surgical resection remains the mainstay of treatment. The optimal surgical procedure for primary tumours is controversial and can vary from wide local excision or endoscopic mucosal resection (EMR) to an abdomino-perineal resection. A high degree of uncertainly exists regarding the benefit of radiation therapy or chemotherapy. The treatment of advanced melanoma is evolving rapidly with better understanding of the disease biology and immunology. Considerable effort has been devoted to the identification of molecular determinants of response to target therapies and immunotherapy.
PubMed: 29492238
DOI: 10.18632/oncotarget.23835 -
Science Advances Sep 2023Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma...
Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn's disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs.
Topics: Animals; Humans; Mice; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Sorting Nexins; Stem Cells
PubMed: 37647408
DOI: 10.1126/sciadv.adh5016 -
Journal of Visceral Surgery Aug 2010Fistula arising from the glands of the anal crypts is the most common form of anoperineal sepsis. It is characterized by a primary internal orifice in the anal canal, a... (Review)
Review
Fistula arising from the glands of the anal crypts is the most common form of anoperineal sepsis. It is characterized by a primary internal orifice in the anal canal, a fistulous tract, and an abscess and/or secondary perineal orifice with purulent discharge. Antibiotics are not curative. The treatment of an abscess is urgent and consists, whenever possible, of incision and drainage under local anesthesia. Definitive treatment of the fistulous tract can await a second stage. The primary aim is to control infection without sacrificing anal continence. Fistulotomy is the basis for all treatments but the specific technique depends on the height of the fistula in relation to the sphincteric mechanism. Overall results of fistulotomy are excellent but there is some risk of anal incontinence. This explains the growing interest in sphincter sparing techniques such as the mucosal advancement flap, the injection of fibrin glue, and the plug procedure. However, results of these procedures are not yet good enough and leave much room for improvement.
Topics: Abscess; Anti-Bacterial Agents; Drainage; Fecal Incontinence; Fibrin Tissue Adhesive; Postoperative Complications; Randomized Controlled Trials as Topic; Rectal Fistula; Risk Factors; Sepsis; Surgical Flaps; Surgical Instruments
PubMed: 20822966
DOI: 10.1016/j.jviscsurg.2010.07.007 -
Clinics in Colon and Rectal Surgery Jan 2022Anorectal strictures are a notoriously difficult to treat phenotype of perianal Crohn's disease. Quality of life is diminished due to ongoing pain, incontinence,... (Review)
Review
Anorectal strictures are a notoriously difficult to treat phenotype of perianal Crohn's disease. Quality of life is diminished due to ongoing pain, incontinence, difficulty with stool evacuation, and recurrent medical and surgical treatments. Medical therapy is aimed at treating luminal disease and mucosal ulceration to prevent worsening of fibrosis. Clinical examination and endoscopic intervention can be used for serial dilations of strictures. Unfortunately, despite optimal medical therapy and endoscopic intervention with serial anal dilations, surgery with intestinal diversion or proctocolectomy may be required as part of the treatment algorithm in a significant proportion of patients.
PubMed: 35069029
DOI: 10.1055/s-0041-1740037 -
Viruses May 2023The main objectives were to describe the prevalence of HPV, its genotypes and HPV-associated dysplastic lesions in the oropharyngeal mucosa of PLHIV and related factors.
BACKGROUND
The main objectives were to describe the prevalence of HPV, its genotypes and HPV-associated dysplastic lesions in the oropharyngeal mucosa of PLHIV and related factors.
MATERIAL AND METHODS
This cross-sectional prospective study consecutively enrolled PLHIV attending our specialist outpatient units. At visit, HIV-related clinical and analytical variables were gathered, and oropharyngeal mucosa exudates were taken to detect HPV and other STIs by polymerase chain reaction. Samples were also taken from the anal canal of all participants and from the genital mucosa of the women for HPV detection/genotyping and cytological study.
RESULTS
The 300 participants had a mean age of 45.1 years; 78.7% were MSM and 21.3% women; 25.3% had a history of AIDS; 99.7% were taking ART; and 27.3% had received an HPV vaccine. HPV infection prevalence in the oropharynx was 13%, with genotype 16 being the most frequent (2.3%), and none had dysplasia. Simultaneous infection with (HR: 4.02 (95% CI: 1.06-15.24)) and a history of anal HSIL or SCCA (HR: 21.52 (95% CI: 1.59-291.6)) were risk factors for oropharyngeal HPV infection, whereas ART duration (8.8 vs. 7.4 years) was a protective factor (HR: 0.989 (95% CI: 0.98-0.99)).
CONCLUSIONS
The prevalence of HPV infection and dysplasia was low in the oropharyngeal mucosae. A higher exposure to ART was protective against oral HPV infection.
Topics: Male; Humans; Female; Middle Aged; Anal Canal; Papillomavirus Infections; HIV Infections; Homosexuality, Male; Cross-Sectional Studies; Prospective Studies; Papillomaviridae; Risk Factors; Mucous Membrane; Genotype; Hyperplasia; Oropharynx; Genitalia; Prevalence
PubMed: 37243256
DOI: 10.3390/v15051170 -
World Journal of Gastrointestinal... Feb 2019Stevens - Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is a severe adverse drug reaction associated with involvement of skin and mucosal membranes, and... (Review)
Review
Stevens - Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is a severe adverse drug reaction associated with involvement of skin and mucosal membranes, and carries significant risk of mortality and morbidity. Mucus membrane lesions usually involve the oral cavity, lips, bulbar conjunctiva and the anogenitalia. The oral/anal mucosa and liver are commonly involved in SJS or TEN. However, intestinal involvement is distinctly rare. We herein review the current literature regarding the gastrointestinal involvement in SJS or TEN. This review focuses mainly on the small bowel and colonic involvement in patients with SJS or TEN.
PubMed: 30788030
DOI: 10.4253/wjge.v11.i2.115