Search

C3 glomerulopathy is a complement-mediated renal disease that is frequently associated with abnormalities in regulation of the complement alternative pathway. Mice with deficiency of factor H (Cfh(-/-)), a negative alternative pathway regulator, are an established experimental model of C3 glomerulopathy in which complement C3 fragments including iC3b accumulate along the glomerular basement membrane. Here we show that deficiency of complement receptor 3 (CR3), the main receptor for iC3b, enhances the severity of spontaneous renal disease in Cfh(-/-) mice. This effect was found to be dependent on CR3 expression on bone marrow-derived cells. CR3 also mediated renal protection outside the setting of factor H deficiency, as shown by the development of enhanced renal injury in CR3-deficient mice during accelerated nephrotoxic nephritis. The iC3b-CR3 interaction downregulated the proinflammatory cytokine response of both murine and human macrophages to lipopolysaccharide stimulation in vitro, suggesting that the protective effect of CR3 on glomerular injury was mediated via modulation of macrophage-derived proinflammatory cytokines. Thus, CR3 has a protective role in glomerulonephritis and suggests that pharmacologic potentiation of the macrophage CR3 interaction with iC3b could be therapeutically beneficial., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Study Objectives: To determine the relationship between d-dimer (DD) and both proinflammatory and anti-inflammatory cytokine levels, and to confirm the association between DD status and outcomes in critically ill patients., Design: Prospective observational study., Setting: Medical ICU (MICU) of a tertiary care, academic medical center., Patients: Individuals admitted to the MICU., Interventions: Within 24 h of MICU admission, patients had DD status determined and interleukin (IL) levels (IL-6, IL-8, and IL-10) and tumor necrosis factor (TNF)-alpha measured. The strength of the DD level was also noted. Subjects were then monitored prospectively to determine mortality rate and the incidence of organ failure., Measurement and Results: The study cohort included 79 patients (mean age, 65.2 years; 54.5% male patients). DD was present in 53.2% of subjects. The DD reaction was weak (1+) in 15 patients and strong (2+) in 27 patients. The TNF-alpha, IL-6, and IL-8 levels all increased in parallel with the increasing strength of the DD level. IL-10 levels did not differ based on DD status. Similarly, the severity of illness as measured by the APACHE (acute physiology and chronic health evaluation) II score was highest among those with higher DD levels: 24.7 +/- 6.2 for those with 2+ DD vs 17.2 +/- 3.1 and 11.5 +/- 2.7 for those with 1+ DD and no circulating DD, respectively (p < 0.001). For patients lacking DD, the mortality rate was 8.1%, compared to 13.3% and 55.6% for those with 1+ and 2+ DD levels, respectively (p < 0.001). No patient without DD had multisystem organ failure (MSOF) develop, while the incidence of MSOF also increased with increasing DD levels. As a screening test for mortality, the DD performed as well as the APACHE II system., Conclusions: The coagulation system is active in critically ill patients, and DD levels correlate with activation of the proinflammatory cytokine cascade. The absence of a relationship between DD and anti-inflammatory cytokines (IL-10) suggests that the presence of DD may reflect the imbalance between proinflammatory and anti-inflammatory cytokines. DD identifies patients at increased risk for both MSOF and death.

Although the morphine withdrawal syndrome has been well described in the rat, a syndrome having similar characteristics has not been demonstrated following chronic methadone treatment. In this study we describe the behavioral effects produced by naloxone (4 mg/kg sc) following 72 hours of continuous iv infusion of methadone, (12.2 micrograms/kg/min), morphine (12.2 to 97.9 micrograms/kg/min) or saline. The cessation of methadone or morphine but not saline treatment followed by naloxone resulted in graded signs including wet dog shakes, escape attempts, self-stimulation and body weight loss and quantal signs including diarrhea, ear blanching, exophthalmos, ptosis, tachypnea and teeth chattering. These results indicate that this mode of methadone administration produces physical dependence characterized by a morphine-like withdrawal syndrome in the rat.

Evidence from a variety of experimental models has suggested the existence of mu 1, mu 2 and delta binding sites for morphine and the enkephalins in the central nervous system. Additional biochemical experiments now support this concept of a common high affinity site for opiates and opioid peptides. Mu sites have now been implicated in a number of pharmacological actions, including supraspinal analgesia, prolactin release, and catalepsy, but not in others (spinal analgesia, respiratory depression, and the guinea pig ileum). The hypothesis of mu 1 sites was supported by the unique opioid meptazinol, which selectively bound to mu 1 sites. As expected from its mu 1 binding selectivity, its analgesic actions in the mouse, localized supraspinally, were antagonized by the selective mu 1 antagonist naloxonazine and it had no respiratory depressant actions. Other binding studies suggested the presence of discrete SKF10,047-selective (KD approximately 5 nM) binding sites in rat brain which differed from both kappa sites and the previously reported PCP-binding sigma sites. Additional binding and autoradiographical studies have also implied the presence of beta-endorphin, or epsilon, sites in the CNS.

The 14-hydroxydihydromorphinone hydrazones have been quite useful in studying aspects of opiate receptor binding and function. The most extensively studied, naloxazone, effectively and selectively inhibits high affinity (mu1) sites in vitro and morphine analgesia in vivo. We now report on the actions of oxymorphazone on receptor binding in vitro and on analgesia in vivo. Oxymorphazone effectively lowers 3H-opioid binding despite extensive washes with the same selectively for high affinity, or mu1, binding sites as naloxazone. Acutely, oxymorphazone was less potent in vivo than oxymorphone (ED50's of 0.8 and 0.4 mg/kg, respectively). Both quantal dose response curves were parallel. At higher doses (100 mg/kg), 83% of animals given oxymorphazone over 20 hr previously were analgesic whereas none of the oxymorphone animals were (p less than 0.001). Oxymorphazone also produced prolonged analgesia after icv administration. These results, in addition to other studies, suggest that oxymorphazone's actions cannot be adequately explained by pharmacokinetic differences from oxymorphone and supports the hypothesis that the drug works via prolonged receptor binding.

To determine whether the differences in development of acute tolerance to several morphine actions correlate with the mu receptor subtype mediating them, we have examined the appearance of acute tolerance to analgesia, respiratory depression, gastrointestinal transit, and hormone release in an intravenous morphine infusion model. Analgesia, a naloxonazine-sensitive mu1 action, peaked at 2 hr after initiation of the infusions. The log dose-response relationship of the infusion rate to peak tailflick latency was linear from 10 to 50 micrograms/kg/min. By 8 hr, the tailflick latencies declined nearly to baseline levels, implying the rapid development of tolerance. Tolerance to morphine-induced prolactin release, another mu1 action, also developed rapidly over 8 hr. In contrast two mu2 actions, respiratory depression measured with arterial blood gas, determinations and gastrointestinal transit, showed no significant tolerance over a similar 8 hr infusion. We also observed no tolerance to morphine-induced growth hormone release, a non-mu1 action, over the same period. Thus, these results demonstrate that mu1 actions develop tolerance in an infusion model far more rapidly than a number of naloxonazine-insensitive (non-mu1) ones and may help explain differences in the rate of tolerance development to morphine actions.