Intrarectal administration of oxygenated perfluorodecalin promotes healing of murine colitis by targeting inflammatory hypoxia

Abstract

Intestinal inflammation is associated with enhanced mucosal hypoxia, which contributes to the ongoing inflammatory process and hampers appropriate mucosal healing. We questioned whether local treatment with an oxygen (O 2 )-carrying and -releasing molecule (oxygenated perfluorodecalin, O 2 -PFD) could positively influence the course of experimental colitis. The impact of intrarectal (IR) treatment with O 2 -PFD was tested using the murine dextran sodium sulfate (DSS)-induced model of distal colitis, both in preventive and therapeutic settings. Colonic mucosal hypoxia was visualized by pimonidazole staining. Colonic permeability was evaluated with FITC-dextran. In the preventive study, mice treated with O 2 -PFD were protected against DSS colitis compared with saline-treated mice, as demonstrated by reduced shortening of colon length, reduced colonic tumor necrosis factor-alpha levels and a lower histological inflammation score (Po0.05 for all parameters). In the therapeutic study, administration of O 2 -PFD resulted in accelerated recovery of colitis compared with saline-treated littermates, and this was reflected by a better weight evolution, lower myeloperoxidase activity and a lower histological inflammation score (Po0.05 for all parameters). It was found that O 2 -PFD established its therapeutic effects through (1) intrinsic anti-inflammatory effects of the PFD molecule and (2) O 2 -induced preservation and healing of the intestinal epithelial surface. Further in vitro and in vivo studies showed that the barrier-protective activity of O 2 -PFD was obtained through prevention of colonocyte apoptosis and stimulation of colonocyte proliferation during inflammatory hypoxia. These data show that IR treatment with O 2 -PFD promotes colitis healing by the combined actions of direct anti-inflammatory effects and O 2 -induced restitution of the epithelial barrier. As such, O 2 -PFD enemas could be an attractive treatment option for patients with distal inflammatory bowel disease.

The Response of Macrophages and Neutrophils to Hypoxia in the Context of Cancer and Other Inflammatory Diseases

“…It is reasonable to assume that the molecular mechanisms that fine-tune the hypoxia-inflammation circle represent attractive targets for the treatment of chronic, nonresolving inflammation. The latter notion is further supported by alleviation of experimental colitis via delivery of oxygen [ 21 , 22 ].…”

Panax notoginseng attenuates hypoxia-induced glycolysis in colonic mucosal epithelial cells in DSS-induced colitis

“…Hypoxia in the colonic mucosa significantly inhibits the normal aerobic oxidation of glucose and increases the anaerobic glycolysis in cmECs (23). Additionally, research has shown that with the aggravation of hypoxia in the colonic mucosa, the apoptosis and necrosis of cmECs increase significantly, both of which are positively correlated to the severity of UC (24,25). This study showed that intracellular glycolysis in cmECs was significantly enhanced, and hypoxia was aggravated in the colonic mucosa in colitis.…”

Imaging assessment of cardioprotection mediated by a dodecafluoropentane oxygen-carrier administered during myocardial infarction

“…In 15 rats with LCA ligation, we administered a single dose (0.6 mL/kg) of 2% DDFPe intravenously at 10 min after LCA ligation. The treatment dose was derived from that used in animal models reported previously [3-6,8-12]. The dose and administration schedules were preliminarily verified in our pilot studies, in which no adverse events, such as animal death or difficulty in recovery from surgery and anesthesia, were encountered.…”

“…Such properties allow DDFPe to deliver many times the oxygen content of liquid perfluorocarbon and can compensate for up to 90% of the oxygen deficiency. Significant reduction of cerebral infarct size in rat and rabbit stroke models has been achieved by single or repeated doses of DDFPe [4-6,8-14]. In a study of a mouse model with MI, caused by irreversible permanent occlusion of the left anterior descending (LAD) coronary artery, DDFPe was administered prior to the coronary occlusion and shown to be able to elicit a cardioprotective effect that persisted well beyond the assumed elimination time of DDFPe [3].…”