Effect of pharmacologically induced smooth muscle activation on permeability in murine colitis.

BACKGROUND: Both intestinal permeability and contractility are altered in inflammatory bowel disease. Little is known about their mutual relation. Therefore, an in vitro organ bath technique was developed to investigate the simultaneous effects of inflammation on permeability and smooth muscle contractility in different segments of the colon. METHODS AND MATERIALS: BALB/c mice were exposed to a 10% dextran sulphate sodium drinking water solution for 7 days to induce a mild colitis, while control mice received normal tap water. Intestinal segments were placed in an oxygenated organ bath containing Krebs buffer. Permeability was measured by the transport of the marker molecules 3H-mannitol and 14C-polyethyleneglycol 4000. Contractility was measured through a pressure sensor. Smooth muscle relaxation was obtained by salbutamol and l-phenylephrine, whereas contraction was achieved by carbachol and 1-(3-chlorophenyl)-biguanide. RESULTS: The intensity of mucosal inflammation increased throughout the colon. Also, regional differences were observed in intestinal permeability. In both normal and inflamed distal colon segments, permeability was diminished compared with proximal colon segments and the non-inflamed ileum. Permeability in inflamed distal colon segments was significantly decreased compared with normal distal segments. Pharmacologically induced relaxation of smooth muscles did not affect this diminished permeability, although an increased motility positively affected permeability in inflamed and non-inflamed distal colon. CONCLUSIONS: Inflammation and permeability is inversely related. The use of pro-kinetics could counteract this disturbed permeability and, in turn, could regulate the disturbed production of inflammatory mediators

Anti-inflammatory actions of acupuncture.

Acupuncture has a beneficial effect when treating many diseases and painful conditions, and therefore is thought to be useful as a complementary therapy or to replace generally accepted pharmacological intervention. The attributive effect of acupuncture has been investigated in inflammatory diseases, including asthma, rhinitis, inflammatory bowel disease, rheumatoid arthritis, epicondylitis, complex regional pain syndrome type 1 and vasculitis. Large randomised trials demonstrating the immediate and sustained effect of acupuncture are missing. Mechanisms underlying the ascribed immunosuppressive actions of acupuncture are reviewed in this communication. The acupuncture-controlled release of neuropeptides from nerve endings and subsequent vasodilative and anti-inflammatory effects through calcitonine gene-related peptide is hypothesised. The complex interactions with substance P, the analgesic contribution of beta-endorphin and the balance between cell-specific pro-inflammatory and anti-inflammatory cytokines tumour necrosis factor-alpha and interleukin-10 are discussed

Six Years Follow-up of the Levels of TNF-α and IL-6 in Patients with Complex Regional Pain Syndrome Type 1

In an earlier study, levels of the proinflammatory cytokines TNF-α and IL-6 are higher in blisters fluid from the complex regional pain syndrome type 1 (CRPS1) side obtained at 6 and 30 months (median) after the initial event. The aim of this follow-up study is to determine the involvement of these cytokines in long lasting CRPS1. Twelve CRPS1 patients, with median disease duration of 72 months, participated. The levels of TNF-α and IL-6 were measured in blister fluid; disease activity was reevaluated by measuring pain and differences in temperature, volume, and mobility between both extremities. Differences in levels of IL-6 and TNF-α and mobility between both sides were significantly decreased. Pain and differences in temperature and volume were not significantly altered. No correlation was found between the cytokines and the disease characteristics. These results indicate that IL-6 and TNF-α are only partially responsible for the signs and symptoms of CRPS1

Effects of carnitine and its congeners on eicosanoid discharge from rat cells: implications for release of TNFα

THE acyl carrier coenzyme A (CoA) is involved in fatty acid metabolism. The carnitine/CoA ratio is of particular importance in regulating the transport of long-chain fatty acids into mitochondria for oxidation. Also CoA has a role in the formation and breakdown of products from both the cyclooxygenase and lipoxygenase pathways of the precursor arachidonic acid. In the present study the effect of 4 days feeding of 300 mg/kg/day of L-carnitine, acetyl Lcarnitine and propionyl L-carnitine on the basal and calcium ionophore (A23187) stimulated release of arachidonic acid metabolites from rat carrageenin elicited peritoneal cells was investigated. There were two series of experiments carried out. In the first, the harvested peritoneal cell population consisted of less than 90% macrophages and additional polymorphonuclear (PMN) leucocytes. The basal release of prostaglandin E2 (PGE2), 6-ketoprostaglandin F1α (6-keto-PGF1α) and leukotriene B4 (LTB4) was stimulated by all treatments. The A23187 stimulated release of 6-keto-PGF1α and LTB4 was increased by all three compounds. The 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 ratios were increased by carnitine treatment. These results suggested that carnitine could modify the macrophage component of an inflammatory site in vivo. In the second series of experiments the harvested cell population was highly purified (>95% macrophages) and none of the compounds fed to the rats caused a change of either eicosanoid or TNFα formation. Moreover the 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 ratios were not enhanced by any of the compounds tested. It is conceivable that in the first series the increased ratios 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 reflected the effect of carnitine or its congeners on PMN leucocytes rather than on macrophages

Intermediate Stage Complex Regional Pain Syndrome Type 1 Is Unrelated to Proinflammatory Cytokines

The aim of this paper is to determine the involvement of tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 in intermediate CRPS 1 as locally formed mediators of inflammation. In this study, 25 patients with proven CRPS 1 (Bruehl criteria) were included. All patients participated in one of our earlier studies during the acute stage of their disease. After the disease developed into an intermediate stage, both the disease activity and the profile of inflammatory mediators were reevaluated. Disease activity and impairment were determined by means of a visual analogue scale, the McGill Pain Questionnaire, the difference in volume and temperature between the involved and uninvolved extremities, and the reduction in active range of motion of the involved extremity. Suction blisters were made on the involved and uninvolved extremities for measurement of IL-6 and TNF-α. A significant improvement in signs and symptoms of impairment was found. However, the levels of IL-6 and TNF-α in blister fluid in the involved extremity versus uninvolved extremity were still significantly raised. Although signs and symptoms are significantly improved, proinflammatory cytokines are still increased in CRPS 1 affected extremities during the intermediate stage of the disease. This indicates that the initiation and sustained development of the disease are only partially affected by proinflammatory cytokines. Follow-up in the chronic stage is necessary to draw more definite conclusions about the existence of a supposed relation between clinical signs and symptoms and the level of proinflammatory cytokines

Cyclic-AMP mediated drugs: differential or global reduction of eicosanoid synthesis in the isolated rat lung?

In this study the question was addressed whether cAMP mediated drugs induce a differential reduction of branches of the arachidonic acid metabolism rather than a global reduction of eicosanoid synthesis. The isolated lungs of actively sensitized rats were employed to study prostaglandin and leukotriene release in the presence and absence of the cAMP mediated drugs theophylline, milrinone, sulmazole, isobutyl-methylxanthine and salbutamol. The release of eicosanoids as measured by RIA was predominantly basal and continuous, with a mild antigen induced stimulation only for TXB2 and the leukotrienes. All drugs reduced eicosanoid release globally. It is concluded that cAMP mediated drugs interfere with arachidonic acid metabolism at a site proximal to the branching into lipoxygenase and cyclo-oxygenase pathways

Inflammatory Profile of Awake Function-Controlled Craniotomy and Craniotomy under General Anesthesia

Background. Surgical stress triggers an inflammatory response and releases mediators into human plasma such as interleukins (ILs). Awake craniotomy and craniotomy performed under general anesthesia may be associated with different levels of stress. Our aim was to investigate whether those procedures cause different inflammatory responses. Methods. Twenty patients undergoing craniotomy under general anesthesia and 20 patients undergoing awake function-controlled craniotomy were included in this prospective, observational, two-armed study. Circulating levels of IL-6, IL-8, and IL-10 were determined pre-, peri-, and postoperatively in both patient groups. VAS scores for pain, anxiety, and stress were taken at four moments pre- and postoperatively to evaluate physical pain and mental duress. Results. Plasma IL-6 level significantly increased with time similarly in both groups. No significant plasma IL-8 and IL-10 change was observed in both experimental groups. The VAS pain score was significantly lower in the awake group compared to the anesthesia group at 12 hours postoperative. Postoperative anxiety and stress declined similarly in both groups. Conclusion. This study suggests that awake function-controlled craniotomy does not cause a significantly different inflammatory response than craniotomy performed under general anesthesia. It is also likely that function-controlled craniotomy does not cause a greater emotional challenge than tumor resection under general anesthesia

Effect of tadalafil on blood flow, pain, and function in chronic cold Complex Regional Pain Syndrome: a randomized controlled trial

Background. This double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity. Methods. Twenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks. The patients also participated in a physical therapy program. The primary outcome measure was temperature difference between the CRPS side and the contralateral side, determined by measuring the skin temperature with videothermography. Secondary outcomes were: pain measured on a Visual Analogue Scale, muscle force measured with a MicroFet 2 dynamometer, and level of activity measured with an Activity Monitor (AM) and walking tests. Results. At the end of the study period, the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group, but there was a significant and clinically relevant reduction of pain in the tadalafil group. Muscle force improved in both treatment groups and the AM revealed small, non-significant improvements in time spent standing, walking, and the number of short walking periods. Conclusion. Tadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction, and deserves further investigation. Trial Registration. The registration number in the Dutch Trial Register is ISRCTN60226869