calcimycin and Wounds-and-Injuries

While exposure of cultured spinal neurons to mild hypothermia provides some protection from physical trauma (dendrotomy), profound cooling (< 17 degrees C) causes unrelated neuronal injury and death, which can be prevented by treatment with NMDA receptor antagonists. To investigate the mechanism of hypothermic neuronal injury we examined the ultrastructure of cultured spinal neurons after 2 h of cooling to 17 degrees C or 10 degrees C, with or without the presence of the NMDA receptor antagonist D-2-amino-5-phosphonovalerate, and with or without rewarming to 37 degrees C. These groups were compared to cultures exposed to NMDA or to the calcium ionophore A23187. Patterns of ultrastructural change, involving cytoskeletal disruption, mitochondrial abnormalities and vacuolization of the cytoplasm, suggest a common mechanism of injury in all treatment groups, involving an elevation of intracellular calcium. Some neurons exposed to hypothermia, NMDA or ionophore developed beaded dendrites. Microtubules were fragmented in varicosities but not in the intervening constrictions; other organelles were largely excluded from the constrictions. Varicosities may form when organelles and cytoplasm accumulate as the result of disruption of transport and membrane stabilizing proteins by proteases activated by calcium influx via NMDA mediated channels. The periodic nature of the swellings may reflect inherently discontinuous distribution of molecular subunits of the cytoskeleton.

Topics: 2-Amino-5-phosphonovalerate; Animals; Calcimycin; Calcium; Cells, Cultured; Cold Temperature; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Ionophores; Mice; Microscopy, Electron; N-Methylaspartate; Neurites; Neurons; Receptors, N-Methyl-D-Aspartate; Stress, Physiological; Wounds and Injuries

Traumatic injury often results in profound immunopathology that can lead to immunosuppression, thereby increasing the morbidity and mortality due to sepsis. The isolation and partial characterization of an immunosuppressive glycopeptide (SAP) from serum of severely burned patients has previously been reported by our laboratory. Recently, this trauma peptide has also been identified in the serum of patients with multiple blunt trauma. This glycopeptide is capable of suppressing neutrophil chemotaxis, T-cell blastogenesis and the lysis of human erythrocytes. We demonstrate in this report that SAP inhibits interleukin 2 (IL-2) biosynthesis by mitogen-stimulated peripheral blood mononuclear cells. Peptide concentrations of 50 nmol and above significantly inhibited IL-2 production. Inhibition was not reduced by the addition of indomethacin or anti-PGE2 to cultures containing greater than 100 nmol of peptide, suggesting that inhibition is not entirely prostaglandin-mediated. Preliminary studies have shown that IL-2 suppression by SAP can be partially reversed by the addition of calcium ionophore. These results suggest a potential immunosuppressive mechanism of the trauma peptide in which T cell blastogenesis is inhibited by interference in IL-2 biosynthesis.

Topics: Calcimycin; Concanavalin A; Glycopeptides; Humans; Interleukin-2; Lymphocyte Activation; Prostaglandins E; T-Lymphocytes; Wounds and Injuries

The present study investigated the effect of the angiotensin-converting enzyme (ACE) inhibitors, captopril, CGS14824A and CGS14831 on in vitro rat aortic and urinary bladder prostacyclin (PGI2; measured as 6-oxo-PGF1 alpha by radioimmunoassay) synthesis. PGI2 synthesis was stimulated with adrenaline (aorta), carbachol (bladder), calcium ionophore A23187, arachidonate and trauma. The ACE inhibitors antagonised adrenaline-, carbachol- and A23187-stimulated PGI2 synthesis in the aorta and bladder (CGS14824A greater than captopril greater than CGS14831) but were without effect on trauma- or arachidonate-stimulated PGI2 synthesis. The patterns of inhibition of these ACE inhibitors, using the same stimulatory regimes, was very similar to those previously observed by us with known calcium channel blockers (nifedipine, verapamil). These data suggest that: (i) ACE inhibitors possess calcium channel blocking properties, which may be of relevance to the antihypertensive action of these drugs; and (ii) ACE inhibitors did not stimulate vascular PGI2 synthesis as has been previously suggested.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arachidonic Acid; Arachidonic Acids; Benzazepines; Calcimycin; Calcium Channel Blockers; Captopril; Carbachol; Epinephrine; Epoprostenol; In Vitro Techniques; Male; Muscle, Smooth; Muscle, Smooth, Vascular; Rats; Rats, Inbred Strains; Urinary Bladder; Wounds and Injuries

The generation and metabolism of leukotrienes (LTs) from polymorphonuclear granulocytes of four polytraumatic patients on stimulation with the Ca-Ionophore A 23187 were studied by high performance liquid chromatography. In contrast to healthy donors the concentration of LTB4 within the supernatant of the stimulated granulocytes from these patients is reduced. The ratio of LTB4 versus the combined amounts of the biologically inactive 6-trans and 12-epi-6-trans-isomers is significantly decreased. In one patient who suffered from an Adult Respiratory Distress Syndrome (ARDS) a pronounced enhancement of LTC4 synthesis was observed.

Topics: Calcimycin; Chromatography, High Pressure Liquid; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Neutrophils; SRS-A; Stereoisomerism; Wounds and Injuries

The present study shows that nifedipine, nimodipine and nisoldipine inhibit in vitro agonist-induced prostacyclin (PGI2) release from rat aortic rings. The agonists used were: U46619 (a thromboxane A2 analogue); A23187 (a calcium ionophore) and adrenaline. In contrast, these calcium channel blockers did not inhibit in vitro trauma- or arachidonic acid (AA)-induced PGI2 release. Therefore, in vitro PGI2 release models may be calcium channel dependent (adrenaline, U46619, A23187) or independent (trauma, AA), a property which is relevant to calcium channel blocker research. It is suggested that calcium channel dependent PGI2 release is relevant to modulating the relaxation phase of muscle contraction, while calcium channel independent PGI2 release is relevant to limiting the extension of thrombi following local vascular trauma.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Calcimycin; Calcium Channel Blockers; Epinephrine; Epoprostenol; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Nicotinic Acids; Nifedipine; Nimodipine; Nisoldipine; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Wounds and Injuries

The role of calcium in the healing of wounds made in the ectoderm of Xenopus neurulae has been studied. Embryos have been wounded in the presence of calcium inhibitors, and the effects on wound healing observed by scanning electron microscopy. In addition, unwounded embryos have been exposed to a local application of ionophore A23187 to simulate the possible calcium fluxes following wounding. Lanthanum, which competes for calcium channels, inhibits wound healing. EDTA, which binds divalent cations, also inhibits wound healing, but its effect can be reversed by the addition of excess calcium. Local application of ionophore A23187, which promotes transport of calcium across biological membranes, results in a local change in cell shapes. These observations lend support to the hypothesis that wound healing in amphibian early embryos, which is effected by changes in cell shapes similar to those seen in certain examples of normal morphogenesis, is initiated by a local influx of calcium into cells.

Topics: Animals; Calcimycin; Calcium; Edetic Acid; Embryo, Nonmammalian; In Vitro Techniques; Lanthanum; Microscopy, Electron, Scanning; Wound Healing; Wounds and Injuries; Xenopus laevis