sirolimus and Intestinal-Diseases

The intestines play a crucial role in the development of sepsis. The balance between autophagy and apoptosis in intestinal epithelial cells is dynamic and determines intestinal permeability. The present study focused on the potential role of autophagy in sepsis-induced intestinal barrier dysfunction and explored the mechanisms in vivo and in vitro. Excessive apoptosis in intestinal epithelia and a disrupted intestinal barrier were observed in septic mice. Promoting autophagy with rapamycin reduced intestinal epithelial apoptosis and restored intestinal barrier function, presenting as decreased serum diamine oxidase (DAO) and fluorescein isothiocyanate-dextran 40 (FD40) levels and increased expression of zonula occludens-1 (ZO-1) and Occludin. Polo-like kinase 1 (PLK1) knockdown in mice ameliorated intestinal epithelial apoptosis and the intestinal barrier during sepsis, whereas these effects were reduced with chloroquine and enhanced with rapamycin. PLK1 also promoted cell autophagy and improved lipopolysaccharide-induced apoptosis and high permeability in vitro. Moreover, PLK1 physically interacted with mammalian target of rapamycin (mTOR) and participated in reciprocal regulatory crosstalk in intestinal epithelial cells during sepsis. This study provides novel insight into the role of autophagy in sepsis-induced intestinal barrier dysfunction and indicates that the PLK1-mTOR axis may be a promising therapeutic target for sepsis.

Topics: Animals; Autophagy; Intestinal Diseases; Intestinal Mucosa; Mammals; Mice; Polo-Like Kinase 1; Sepsis; Sirolimus; TOR Serine-Threonine Kinases

Intestinal ischemia/reperfusion (I/R) is a grave condition related to high morbidity and mortality. Autophagy, which can induce a new cell death named type II programmed cell death, has been reported in some intestinal diseases, but little is known in I/R-induced intestinal injury. In this study, we aimed to explore the role of autophagy in intestinal injury induced by I/R and its potential mechanisms.. The rats pretreated with rapamycin or 3-methyladenine had intestinal I/R injury. After reperfusion, intestinal injury was measured by Chiu's score, intestinal mucosal wet-to-dry ratio, and lactic acid level. Intestinal mucosal oxidative stress level was measured by malondialdehyde and superoxide dismutase. Autophagosome, LC3, and p62 were detected to evaluate autophagy level. Mammalian target of rapamycin (mTOR) was detected to explore potential mechanism.. Chiu's score, intestinal mucosal wet-to-dry ratio, lactic acid level, malondialdehyde level, autophagosomes, and LC3-II/LC3-I were significantly increased, and superoxide dismutase level and expression of p62 were significantly decreased in intestinal mucosa after intestinal ischemia/reperfusion. Pretreatment with rapamycin significantly aggravated intestinal injury evidenced by increased Chiu's score, intestinal mucosal wet-to-dry ratio and lactic acid level, increased autophagy level evidenced by increased autophagosomes and LC3-II/LC3-I and decreased expression of p62, and downregulated expression of p-mTOR/mTOR. On the contrary, pretreatment with 3-methyladenine significantly attenuated intestinal injury and autophagy level and upregulated expression of p-mTOR/mTOR.. In summary, autophagy was significantly enhanced in intestinal mucosa after intestinal ischemia/reperfusion, and inhibition of autophagy attenuated intestinal injury induced by I/R through activating mTOR signaling.

Topics: Adenine; Animals; Autophagy; Drug Evaluation, Preclinical; Intestinal Diseases; Intestinal Mucosa; Male; Malondialdehyde; Random Allocation; Rats, Sprague-Dawley; Reperfusion Injury; Sirolimus; Superoxide Dismutase; TOR Serine-Threonine Kinases

Drug-induced angioedema has been reported as an adverse effect of many different drugs. But small bowel angioedema associated with sirolimus (SRL) used was barely understood. It must be necessary to report a case suffering from small bowel angioedema with detailed discussion and literature review.. A 38-year-old Chinese woman presented with generalized gastric pain in the following day after renal transplantation. The patient began to crampy abdominal pain accompanied by nausea, vomiting, and diarrhea on postoperative day 6 (POD).. We strongly suspected the angioedema was an adverse reaction to SRL.. The immunosuppressive regimen was switched from tacrolimus (TAC), SRL, and prednisone to TAC, mycophenolate and prednisone.. The symptoms were relieved within next 48 hours after withdrawing the SRL. One more CT scan showed complete resolution of bowel wall thickening and ascites.. This was the first report of small bowel angioedema associated with SRL. Drug-induced-angioedema is a relatively common presentation and is potentially fatal. It must be aware of potential adverse effects.

Topics: Adult; Angioedema; Female; Humans; Immunosuppressive Agents; Intestinal Diseases; Intestine, Small; Kidney Transplantation; Postoperative Complications; Sirolimus

This report describes two patients with sporadic lymphangioleiomyomatosis complicated by protein-losing enteropathy (PLE). Imaging studies indicated retroperitoneal lymphangioleiomyomas and abnormalities of the adjacent digestive tract. Endoscopic mucosal biopsy revealed colonic lymphangiectasia in one patient; whereas the site in the other patient was intestinal. Treatment with sirolimus led to the complete resolution of PLE within several months; additionally, marked shrinkage was observed in the lymphangioleiomyomas of both cases. These findings suggest that colonic or intestinal lymphatic congestion due to neighboring lymphangioleiomyomas was the mechanism for the development of PLE. At the time of writing this report, the beneficial effect of sirolimus has lasted for more than 3 years.

Topics: Adult; Colonic Diseases; Diet Therapy; Diet, Fat-Restricted; Female; Humans; Immunosuppressive Agents; Intestinal Diseases; Lymphangiectasis; Lymphangioleiomyomatosis; Protein-Losing Enteropathies; Sirolimus; Treatment Outcome

Acute-phase intestinal ischemia-reperfusion (I-R) injury can result in multiple organ failure, which may sometimes be fatal. However, no reliable treatment for this clinical state is available. Rapamycin has been reported to protect heart, brain and kidney against I-R injury. The aim of this study was to examine whether rapamycin could protect mice against I-R-induced intestinal and remote organ injury.. Ischemia was induced in the intestine of C57BL/6 mice by occluding the superior mesenteric artery for 1 h. Mice received rapamycin at a dose of 5 mg/kg or vehicle by the intraperitoneal injection 1 h before ischemia. The survival rate, inflammatory responses in the intestine and the lung, bacteria cultured from lung tissue and the phagocytic capacity of alveolar macrophages were examined.. Treatment with rapamycin improved survival rate after intestinal I-R. Histological and biochemical parameters of I-R-induced intestinal injury/inflammation were similar in both rapamycin-treated and untreated mice. However, signs of lung injury/inflammation were significantly attenuated in rapamycin-treated mice compared to control mice. The reduction of lung bacteria and the increase in phagocytic activity were accompanied in mice treated with rapamycin.. Rapamycin improved mortality following intestinal I-R via the inhibition of remote lung inflammation in mice.

Topics: Animals; Anti-Bacterial Agents; Inflammation; Injections, Intraperitoneal; Intestinal Diseases; Intestines; Lung; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury; Sirolimus; Survival Rate

Few studies examined the clinicopathologic features of PTLD arising in pediatric SBT patients. Particularly, the association between ATG and PTLD in this population has not been described. Retrospective review of 81 pediatric patient charts with SBT--isolated or in combination with other organs--showed a PTLD incidence of 11%, occurring more frequently in females (median age of four yr) and with clinically advanced disease. Monomorphic PTLD was the most common histological subtype. There was a significant difference in the use of ATG between patients who developed PTLD and those who did not (p < 0.01); a similar difference was seen with the use of sirolimus (p < 0.001). These results suggested a link between the combination of ATG and sirolimus and development of more clinically and histologically advanced PTLD; however, the risk of ATG by itself was not clear. EBV viral loads were higher in patients with PTLD, and median time between detection of EBV to PTLD diagnosis was three months. However, viral loads at the time of PTLD diagnosis were most often lower than at EBV detection, thereby raising questions on the correlation between decreasing viral genomes and risk of PTLD.

Topics: Adolescent; Antilymphocyte Serum; Child; Child, Preschool; Female; Gene Rearrangement; Genome, Viral; Humans; Immunosuppressive Agents; In Situ Hybridization; Infant; Intestinal Diseases; Intestine, Small; Lymphoma; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Risk; Sirolimus; VDJ Recombinases; Viral Load; Young Adult

The mTOR signaling pathway plays a crucial role in the regulation of cell growth, proliferation, survival and in directing immune responses. As the intestinal epithelium displays rapid cell growth and differentiation and is an important immune regulatory organ, we hypothesized that mTOR may play an important role in the protection against intestinal ischemia reperfusion (I/R)-induced injury. To better understand the molecular mechanisms by which the mTOR pathway is altered by intestinal I/R, p70S6K, the major effector of the mTOR pathway, was investigated along with the effects of rapamycin, a specific inhibitor of mTOR and an immunosuppressant agent used clinically in transplant patients. In vitro experiments using an intestinal epithelial cell line and hypoxia/reoxygenation demonstrated that overexpression of p70S6K promoted cell growth and migration, and decreased cell apoptosis. Inhibition of p70S6K by rapamycin reversed these protective effects. In a mouse model of gut I/R, an increase of p70S6K activity was found by 5 min and remained elevated after 6 h of reperfusion. Inhibition of p70S6K by rapamycin worsened gut injury, promoted inflammation, and enhanced intestinal permeability. Importantly, rapamycin treated animals had a significantly increased mortality. These novel results demonstrate a key role of p70S6K in protection against I/R injury in the intestine and suggest a potential danger in using mTOR inhibitors in patients at risk for gut hypoperfusion.

Topics: Animals; Apoptosis; Cell Line; Epithelial Cells; Immunosuppressive Agents; Intestinal Diseases; Intestinal Mucosa; Male; Mice; Rats; Reperfusion Injury; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

To review our experience with SRL as a second-line therapy in our series of 45 SBTx recipients (1997-2009). Retrospective review of five children converted to SRL: 3 M/2 F; median of three yr old (range 20 months-18 yr); rescue indications, adverse events with SRL, resolution of tacrolimus-related side effects, incidence of rejection, PTLD, or GVHD were summarized. Tacrolimus was discontinued (average 13 months after transplant) because of refractory hemolytic anemia in four patients with decreased renal function and because of advanced renal failure and unclear neutropenia in one. PTLD and GVHD had been previously diagnosed in two. Tacrolimus-related side effects disappeared in all five although other immunosuppressants and splenectomy were used simultaneously or later in most of them. Adverse events reported after the conversion were infections (tuberculosis and Pneumocystis carinii in two) and mild hypertriglyceridemia. No rejection, GVHD, or PTLD episode was observed. Four patients are alive with excellent quality of life (median follow-up 18 months). Sirolimus is a safe rescue therapy in SBTx children when tacrolimus is not well tolerated. Renal function and hematologic disorders seem to improve, although other simultaneous strategies could be also involved. Further studies could demonstrate its efficacy as a first-line treatment.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Intestines; Male; Organ Transplantation; Pediatrics; Postoperative Complications; Sirolimus; Treatment Outcome