Gadolinium decreases inflammation related to myocardial ischemia and reperfusion injury

Abstract

BackgroundThe lanthanide cation, gadolinium (GdCl3) protects the myocardium against infarction following ischemia and reperfusion. Neutrophils and macrophages are the main leukocytes responsible for infarct expansion after reperfusion. GdCl3 interferes with macrophage and neutrophil function in the liver by decreasing macrophage secretion of inflammatory cytokines and neutrophil infiltration. We hypothesized that GdCl3 protects against ischemia and reperfusion injury by decreasing inflammation. We determined the impact of GdCl3 treatment for reperfusion injury on 1) circulating monoctye and neutrophil counts, 2) secretion of inflammatory cytokines, and 3) influx of monocytes and neutrophils into the myocardium.MethodsRats (n = 3-6/gp) were treated with saline or GdCl3 (20 μmol/kg) 15 min prior to a 30 min period of regional ischemia and 120 min reperfusion. Sham rats were not subject to ischemia. Blood was collected either after 30 min ischemia or 120 min reperfusion and hearts were harvested at 120 min reperfusion for tissue analysis. Blood was analyzed for leukocytes counts and cytokines. Tissue was analyzed for cytokines and markers of neutrophil and monocyte infiltration by measuring myeloperoxidase (MPO) and α-naphthyl acetate esterase (ANAE).ResultsGdCl3 did not affect the number of circulating neutrophils prior to ischemia. Two hours reperfusion resulted in a 2- and 3- fold increase in circulating monocytes and neutrophils, respectively. GdCl3 decreased the number of circulating monocytes and neutrophils during reperfusion to levels below those present prior to ischemia. Furthermore, after 120 min of reperfusion, GdCl3 decreased ANAE and MPO activity in the myocardium by 1.9-fold and 6.5-fold respectively. GdCl3 decreased MPO activity to levels below those measured in the Sham group. Serum levels of the major neutrophil chemoattractant cytokine, IL-8 were increased from pre-ischemic levels during ischemia and reperfusion in both control and GdCl3 treated rats. Likewise, IL-8 levels increased throughout the 3 hour time period in the Sham group. There was no difference in IL-8 detected in the myocardium after 120 min reperfusion between groups. In contrast, after 120 min reperfusion GdCl3 decreased the myocardial tissue levels of macrophage secreted cytokines, GM-CSF and IL-1.ConclusionGdCl3 treatment prior to ischemia and reperfusion injury decreased circulating monocytes and neutrophils, macrophage secreted cytokines, and leukocyte infiltration into injured myocardium. These results suggest GdCl3 decreased monoctye and neutrophil migration and activation and may be a novel treatment for inflammation during ischemia and reperfusion.

Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats

“…In this study, we found that lowdose GdCl 3 dramatically inhibited AA-induced Ca 2+ overload and elevated resting [Ca 2+ ] i in A/R NRVMs ( Figure 3B-E). We also demonstrated that low-dose GdCl 3 significantly ameliorates I/R-induced cytochrome c release in vivo ( Figure 5H) and in vitro ( Figure 3A) and inhibits cell apoptosis via regulation of Previous studies have demonstrated that pathophysiological responses triggered after reperfusion include the release of activation factors and free radicals, which activate phospholipase A 2 and increase AA release [24] . The accumulated AA in the myocardium may play an important role in post-I/R injury because a time-dependent degradation of membrane phospholipids associated with an increase in membrane permeability was observed in the ischemic myocardium [17,38] .…”

“…GdCl 3 (10 mg/kg) has been demonstrated to exert a protective potential in I/R-induced brain injury and hepatic injury and to protect the myocardium against I/R-induced inflammation via the reduction of circulating monocytes and neutrophils and the infiltration of leukocytes. This dose also attenuated myocardial stunning when administered prior to the onset of ischemia or during ischemia, but it did not enhance the contractile function of normal myocardium [21][22][23][24] . However, the precise mechanism(s) underlying the effect of GdCl 3 are not known.…”

Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury

“…These results indicated a critical role of M1 microglia/macrophages in inducing the necroptosis of astrocytes after SCI. Considering that GdCl 3 also affects neutrophils [ 38 ], which are abundant in the injury epicenter after SCI, and that iNOS can also be expressed by neutrophils [ 39 ]. The beneficial effects of GdCl 3 treatment may also be contributed by the inhibition of neutrophils.…”

Postconditioning with α7nAChR Agonist Attenuates Systemic Inflammatory Response to Myocardial Ischemia–Reperfusion Injury in Rats

“…Recent experiments demonstrate that inflammation plays a major role in ischemia-reperfusion injury (IRI) [1][2][3], and anti-inflammatory treatment provides protection against myocardial IRI [4,5]. It is generally believed that production and release of proinflammatory cytokines can be regulated by specifically augmenting cholinergic signaling via the efferent vagus nerve and the α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) [6].…”