Abstract
Thrombosis and inflammation cooperate in the development of intestinal infarction. Recent studies suggest that extracellular DNA released by damaged cells or neutrophils in form of extracellular traps (NETs) contributes to organ damage in experimental models of ischemia-reperfusion injury. Here we compared the therapeutic effects of targeting fibrin or extracellular DNA in intestinal infarction after midgut volvulus in rats. Following iatrogenic midgut volvulus induction for 3 hours, we treated animals with a combination of tissue plasminogen activator (tPA) and low molecular weight heparin (LMWH) to target fibrin or with DNase1 to degrade extracellular DNA. The therapeutic effects of tPA/LMWH and DNase1 were analyzed after 7 days. We observed that both therapeutic interventions ameliorated tissue injury, apoptosis, and oxidative stress in the intestine. DNase1, but not tPA/LMWH, reduced intestinal neutrophil infiltration and histone-myeloperoxidase-complexes, a surrogate marker of NETs, in circulation. Importantly, tPA/LMWH, but not DNase1, interfered with hemostasis as evidenced by a prolonged tail bleeding time. In conclusion, our data suggest that the therapeutic targeting of fibrin and extracellular DNA improves the outcome of midgut volvulus in rats. DNase1 therapy reduces the inflammatory response including NETs without increasing the risk of bleeding. Thus, targeting of extracellular DNA may provide a safe therapy for patients with intestinal infarction in future.
Highlights
Midgut volvulus refers to a condition in which the midgut twists around the axis of the superior mesenteric artery, a disorder with a reported annual incidence of 1.7–5.7:1000001
We observed a significant increase in circulating extracellular DNA within 4 hours post midgut volvulus, when compared to controls (Fig. 1B)
The neonatal intestine is highly susceptible to Ischemia and reperfusion (IR) injury, understanding the pathomechanism of IR injury is crucial[34]
Summary
Midgut volvulus refers to a condition in which the midgut twists around the axis of the superior mesenteric artery, a disorder with a reported annual incidence of 1.7–5.7:1000001. One hour after detorsion and thrombolysis (LMWH/tPA) or active (DNase1) or inactivated DNase[1] (Control) treatment, animals were placed in prone position and a 1 cm segment of the tail was amputated at the distal end using a scalpel. To determine whether extracellular DNA and fibrin are being generated following midgut volvolus in rats, we collected plasma after two, four, and six hours of volvulus as well as from sham-operated controls (Fig. 1A).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
