Endothelins are angiogenic.

Endothelins-1 and 3 (ET-1 and 3) were evaluated for angiogenesis in the rat cornea. Bisected 2 mm pellets containing 20-1000 ng of ET-1 or ET-3 in Hydron were placed in corneal micro-pockets. Murine vascular endothelial growth factor (VEGF) and human interleukin-8 (IL-8) were positive controls. No angiogenesis occurred in 32 corneas with pellets containing only saline. With 200 ng VEGF pellets, 27/52 corneas (52%) demonstrated angiogenesis. With 200 ng IL-8 pellets, 32/51 corneas (63%) demonstrated angiogenesis. With 20-1000 ng ET-1 pellets, angiogenesis occurred in 65/91 corneas (71%); with ET-3 pellets, 84/116 (72%). ET-1- and ET-3-mediated angiogenesis was unaffected by cyclophosphamide-induced leukopenia. ET-1-mediated angiogenesis was inhibited by an ET(A)-receptor antagonist (ra) (BQ610) and a combined ET(A)/ET(B) ra (bosentan). However, ET-1-mediated angiogenesis was not inhibited by an ET(B) ra(BQ788) and a weak ET(A) ra(BQ123). Thus, ET-1 and -3 are angiogenic in the rat cornea; this effect appears to be direct, not leukocyte-mediated, and ET(A)-receptor-dependent.

Cardiopulmonary bypass increases coronary IL-8 in diabetic patients without evidence of reperfusion injury.

BACKGROUND: Endothelin-1 (ET-1) has been shown to be a potent agonist for monocyte production of the neutrophil chemotactic cytokine interleukin-8 (IL-8). We have shown that diabetic patients demonstrate elevated coronary ET-1 after coronary artery bypass grafting (CABG). We hypothesized that these same diabetic patients would manifest elevated coronary IL-8 and conjugated diene concentrations (an index of reperfusion injury). METHODS: Sixteen patients [9 nondiabetics and 7 type II diabetics] underwent nonemergent CABG. The two groups did not differ significantly in preoperative ejection fraction, number of vessels bypassed, or cross-clamp time. Coronary sinus samples were obtained prior to cardioplegic arrest (baseline) and at 1 and 15 min after reperfusion periods A and B (A, reperfusion of native coronaries + LIMA; B, reperfusion of saphenous vein grafts in addition to native coronary system + LIMA). Plasma samples were analyzed for IL-8 (ELISA) and conjugated dienes (spectrophotometry). RESULTS: Initially after reperfusion, IL-8 in both groups was significantly lower than precardioplegia values. In reperfusion B, only the diabetic group demonstrated a significant increase in IL-8 concentrations at 1 and 15 min compared to nondiabetics. Conjugated diene levels were significantly higher in diabetics at each time point than nondiabetics. CONCLUSIONS: This study demonstrates an early decrease in IL-8 in both groups, most likely related to depressed production secondary to hypothermia. The subsequent elevation in IL-8 only in the diabetic group was seen without concomitant conjugated diene elevation. While no evidence of reperfusion injury was demonstrated in this time frame, the elevation of IL-8 in diabetics after CABG may contribute to later infiltration and associated oxidative damage.

Evaluation of abdominal pain in systemic lupus erythematosus.

BACKGROUND: Abdominal pain is a common finding in patients with systemic lupus erythematosus (SLE), occurring in as many as half of all SLE patients in the course of their disease. The rheumatology and gastroenterology literature emphasizes etiologies of abdominal pain in patients with SLE such as peritonitis from polyserositis, dyspepsia from reflux, nausea and vomiting from bowel edema, ascites, mesenteric ischemia, pancreatitis, pneumatosis intestinalis from necrotizing enterocolitis, and hepatobiliary abnormalities. But in clinical practice, caring for SLE patients in a community teaching hospital, these seem to be rare entities. PATIENTS AND METHODS: A chart review study was performed of all patients with SLE with the diagnosis of abdominal pain admitted to a community teaching hospital between 1980 and 1995. RESULTS: Of 13 patients who presented with abdominal pain, 9 required surgical intervention for cholecystitis, perforated ulcer, colonic perforation, diverticulitis, and adhesions. There were no negative laparotomies for polyserositis or bowel edema, or cases of mesenteric infarction or ascites. CONCLUSION: Despite some unusual diagnostic possibilities in abdominal pain in SLE such as polyserositis and mesenteric infarction, and despite the superimposed problems of steroid therapy in most of the patients in this study, the majority of lupus patients with abdominal pain presenting at community hospitals have relatively conventional illnesses.

Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis.

The relative contributions of microvascular inflammation and vasomotor dysregulation to the development of acute vaso-occlusive crisis in sickle cell disease have been intensely studied. The present observational study was designed to examine the levels of circulating proinflammatory cytokines, anti-inflammatory cytokines, and vasoactive mediators during and after acute painful crisis. In symptomatic sickle cell patients, plasma levels of endothelin-1 and prostaglandin E2 were elevated during crises compared with healthy African-American controls. These levels had decreased, but not normalized, when patients were seen 1 to 3 weeks after discharge from hospital. Other mediators (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], IL-6, IL-8, and IL-10) were neither elevated in asymptomatic sickle cell disease nor in acute vaso-occlusive crisis. As a potent long-acting mediator of vasoconstriction and inflammation, endothelin-1 may play a key role in the cycle of ischemia and inflammation that initiates and sustains pain of crisis. The downregulatory effects of prostaglandin E2 on immune cell function may contribute to the increased susceptibility to infection observed in patients with sickle cell disease.

Uterine closure with the endo stitch 10-mm laparoscopic suturing device--a review of 50 laparoscopic myomectomies.

OBJECTIVE: To evaluate the mechanical performance of the Endo Stitch Laparoscopic Suturing Device and the clinical effectiveness of both a running, locked suture technique and a new modified suture technique for closure of uterine defects after laparoscopic removal of myomas. STUDY SUBJECTS: Fifty consecutive patients with symptomatic uterine leiomyomata. OBSERVATIONAL METHOD: Retrospective chart review. MAIN FINDINGS: The endometrial cavity was entered and sutured laparoscopically, in two layers, in 22 patients. In 28 patients, only the myometrium was sutured. A two-layered closure of the endometrium and myometrium was completed in an average time of 10 minutes. Mechanical problems with the Endo Stitch occurred in 11 cases. In all patients with second-look laparoscopies, the fallopian tubes were patent bilaterally without adhesions. No uterine fistulas were present in any patients with second-look laparoscopies. Posterior myomas were removed and sutured without adhesion formation. Grade 3 adhesions, to the uterine surface, were associated with transverse incisions of the uterus and over-treatment with GnRH analogs. CONCLUSIONS: The Endo Stitch Laparoscopic Suturing Device in combination with a running, locked suture technique achieves a rapid, hemostatic, clinically secure closure of the endometrium and myometrium. The Endo Stitch and our modified suture technique were not associated with adhesions or blockage of the fallopian tubes or uterine fistulas following laparoscopic myomectomies. The initial mechanical problems with the Endo Stitch were resolved. In our experience, currently the Endo Stitch is the best instrument for laparoscopic suture closure of uterine defects.

Endothelin-1 and endothelin-4 stimulate monocyte production of cytokines.

OBJECTIVE: To determine the effect of endothelin-1 and endothelin-4 on human monocyte production of cytokines. DESIGN: Previous work from our laboratory has shown that endothelin-1 activates leukocytes. Endothelin-1 and endothelin-3 are principally produced by vascular endothelium. However, epidermal cells in gut mucosa, lung, and kidney produce endothelin-2 and endothelin-4, which differ by a single amino acid. While structurally similar to endothelin-1, endothelin-2 and endothelin-4 may affect gut smooth muscle and other tissues differently. The effect of endothelin-1 and endothelin-4 was examined on monocyte production of interleukins (IL) and neutrophil activation factors. SETTING: A clinically-oriented basic science laboratory in a Veterans Administration Hospital and Medical Center. SUBJECTS: Healthy volunteer adult male/female medical students, researchers, and hospital workers. INTERVENTIONS: Human peripheral blood mononuclear cells were separated on density gradients and cultured in media, with or without the addition of bacterial endotoxin or varying molar concentrations of endothelin-1 and endothelin-4. Supernatants were harvested at 10 mins, and at 1, 6, 12, 24, and 48 hrs, and enzyme-linked immunosorbent assays were performed to determine the presence of tumor necrosis factor-alpha, IL-1 beta, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor. MEASUREMENTS AND MAIN RESULTS: Endothelin-1 and endothelin-4 were potent stimuli for monocyte production of tumor necrosis factor-alpha, IL-8, and granulocyte-macrophage colony-stimulating factor. They also caused IL-1 beta and IL-6 production. CONCLUSIONS: Endothelin-1 and endothelin-4 may activate leukocytes after shock or gut ischemia, resulting in further injury to reperfused tissues and distant injury to lungs and other organs.

Endothelin-1, interleukin-6, and interleukin-8 levels increase in patients with burns.

Endothelin is produced by injured or ischemic endothelium and causes monocyte production of interleukins-6 and 8 in vitro. Endothelin levels increase in patients with burn injuries, and we asked whether interleukin-6 and 8 levels increased in patients with burn injuries concurrently with endothelin. Fourteen patients with more than 20% body surface area burns were resuscitated to maintain urine output of 0.5 to 1.0 ml/kg/hr. Blood was drawn on admission and at 12, 24, and 48 hours. Endothelin was measured by radioimmunoassay, interleukins-6 and 8 were measured by enzyme-linked immunosorbent assay. Endothelin levels increased to 6.1 +/- 2.3 fmol on admission, 5.7 +/- 2.1 at 12 hours, 6.9 +/- 2.7 at 24 hours, and 6.4 +/- 2.7 at 48 hours (vs 0.5 in healthy controls). Interleukin-6 increased to 243 +/- 220 pg/ml on admission, 276 +/- 198 at 12 hours, 400 +/- 282 at 24 hours, and 379 +/- 274 at 48 hours (vs less than 50 in healthy controls). Interleukin-8 increased to 504 +/- 309 pg/ml on admission, 483 +/- 263 at 12 hours, 575 +/- 306 at 24 hours, and 698 +/- 667 at 48 hours (vs less than 50 in controls). Endothelin-1 and interleukin-6 and 8 levels increase in patients with burn injuries. Endothelin-mediated activation of monocytes that cause cytokine production may have clinical relevance in patients with burn injuries.