Mesenteric ischemia-reperfusion injury up-regulates certain CC, CXC, and XC chemokines and results in multi-organ injury in a time-dependent manner.

INTRODUCTION: Trauma patients who develop multi-organ dysfunction have increased systemic levels of chemotactic cytokines. Ischemia-reperfusion (IR) injury to the gut may play a role. The purpose of this study was to examine chemokine production in a mouse model of mesenteric IR injury. Given the pre-eminent role of the neutrophil, there has been much investigation of the CXC chemokines, but very limited research on the CC and XC chemokines. We hypothesized that intestinal IR injury would induce remote organ injury and enhance serum CC and XC chemokine levels. METHODS: Fasted female C57BL6 mice were anesthetized prior to laparotomy. In IR animals, the superior mesenteric artery (SMA) was occluded for 30, 45, or 75 min, while controls underwent sham laparotomy, n = 5-7 per group. After the indicated time point, the incision was closed and the mouse was allowed to recover for six hours. Following euthanasia, serum levels of 15 chemokines (10 CC, 4 CXC, and 1 XC) were assessed and histopathologic analyses performed. RESULTS: Seventy-five minutes of SMA occlusion was the key time frame for significant serum cytokine level up-regulation, intestinal and remote organ injury, and neutrophil influx into tissues. With 75 min of intestinal ischemia, significantly elevated serum levels, as compared to shams, were noted for seven CC chemokines: MCP-1, MCP-3, MIP-1ß, MIP-3ß, eotaxin, MDC, and RANTES. Levels of the XC chemokine lymphotactin also increased. Levels of MIP-2, IP-10, and KC/GRO (CXC chemokines) rose significantly. MIP-1α levels were only significantly increased at 45 min IR. We did not find any significant IR injury-induced changes in levels of MCP-5, MIP-1γ, or GCP-2, at any ischemia time frame. Serum levels of IL-6 correspondingly increased significantly with longer ischemia times. CONCLUSIONS: The novel finding of this study is the demonstration of significant systemic increases in the CC chemokines eotaxin, MCP-3, MDC, MIP-3ß in a time-dependent manner, along with tissue injury. The data suggest a complex response to IR injury whereby chemokines that are active on a variety of leukocytes may play a role in inducing local and remote tissue injury.

Methamphetamine administration targets multiple immune subsets and induces phenotypic alterations suggestive of immunosuppression.

Methamphetamine (Meth) is a widely abused stimulant and its users are at increased risk for multiple infectious diseases. To determine the impact of meth on the immune system, we utilized a murine model that simulates the process of meth consumption in a typical addict. Our phenotypic analysis of leukocytes from this dose escalation model revealed that meth affected key immune subsets. Meth administration led to a decrease in abundance of natural killer (NK) cells and the remaining NK cells possessed a phenotype suggesting reduced responsiveness. Dendritic cells (DCs) and Gr-1(high) monocytes/macrophages were also decreased in abundance while Gr-1(low) monocytes/macrophages appear to show signs of perturbation. CD4 and CD8 T cell subsets were affected by methamphetamine, both showing a reduction in antigen-experienced subsets. CD4 T cells also exhibited signs of activation, with increased expression of CD150 on CD226-expressing cells and an expansion of KLRG1(+), FoxP3(-) cells. These results exhibit that meth has the ability to disrupt immune homeostasis and impact key subsets of leukocytes which may leave users more vulnerable to pathogens.

Inhalation of tobacco smoke induces increased proliferation of urinary bladder epithelium and endothelium in female C57BL/6 mice.

Cigarette smoking is the major environmental risk factor for bladder cancer in humans. Aromatic amines, potent DNA-reactive bladder carcinogens present in cigarette smoke, contribute significantly. However, increased cell proliferation, caused by direct mitogenesis or in response to cytotoxicity, may also play a role since urothelial hyperplasia has been observed in human cigarette smokers. We examined the urothelial effects of cigarette smoke (whole body inhalation exposure (Teague) system) in female C57BL/6 mice at various times in two studies, including reversibility evaluations. In both studies, no urothelial hyperplasia was observed by light microscopy in any group. However, in study 1, the Ki-67 labeling index (LI) of the urothelium was significantly increased in the smoke exposed group compared to controls through 3 months, but was not present at 6, 9 or 12 months even with continued exposures. In the groups that discontinued smoke exposure, it returned to the same levels as controls or lower. In study 2, the bromodeoxyuridine LI was similar to controls on day 1 but significantly increased at 5 days in the smoke exposed group. In the group that discontinued smoke exposure for 2 days, the LI was increased compared to controls but not significantly. Superficial urothelial cell cytotoxicity and necrosis were detectable by scanning electron microscopy at 5 days. Changes in LI of submucosal endothelial cells generally followed those of the urothelium and effects were reversible upon cessation of exposure. The increased urothelial proliferation appeared to be due to superficial cell cytotoxicity with consequent regeneration.