Novel model of peripheral tissue trauma-induced inflammation and gastrointestinal dysmotility

Abstract

Background Trauma is a leading cause of death and although the gut is recognized as the “motor” of post-traumatic systemic inflammatory response syndrome and multiple organ failure, studies on the gastrointestinal tract are few. Our objectives were to create a precisely controllable tissue injury model in which gastrointestinal motility, systemic inflammation and wound fluid can be analyzed. Methods A non-narcotic murine trauma model was developed by the subcutaneous dorsal trans-implantation of a devitalized donor syngeneic harvested tissue-bone matrix (TBX), which was precisely adjusted to % total body weight and studied after 21 hrs. Gastrointestinal transit histograms were plotted after the oral administration of non-digestible FITC-dextran and geometric centers calculated. Organ bath evaluated jejunal circular muscle contractility. Multiplex electrochemiluminescence measurements of serum and TBX wound fluid inflammatory mediators were performed. Key Results Increasing TBX amounts progressively delayed transit, whereas TBX heat denaturation or decellularization prevented ileus and death. In the TBX17.5% model, jejunal muscle contractility was suppressed and a systemic inflammatory response developed as significant serum elevations in IL-6, keratinocyte cytokine and IL-10 compared to sham. Additionally, inflammatory responses within the wound fluid showed elevated levels of preformed IL-1β and TNF-α, whereas, 21 hours after implantation IL-1β, IL-6 and keratinocyte cytokine were significantly increased in the wound. Conclusions & Inferences A novel donor tissue-bone matrix trauma model was developed that is precisely adjustable and recapitulates important clinical phenomena. The non-narcotic model demonstrated that increasing tissue injury progressively caused ileus, initiated a systemic inflammatory response and developed inflammatory changes within the wound.

Development of A Novel Murine Model of Combined Radiation and Peripheral Tissue Trauma Injuries

“…The peripheral tissue trauma model was described previously (15). Briefly, long bones, including muscles and rib cage with intercostal muscles, were isolated and minced (yielding TBX), and then implanted in the subcutaneous pouch of a healthy, syngenic, recipient mouse through a small (1 cm) incision.…”

“…Animals were irradiated using a Precision X-ray 320 irradiator (North Branford, CT) at dose of 12.6 Gy (320 kV, 12.5 mA; 2 mm aluminum filter; HVL ~ 1 mm copper) and a dose rate of 1.58 Gy/min. Immediately after irradiation, mice were anesthetized with Isoflurane (Primal Healthcare Limited, Bethlehem, PA) and the surgical procedure for TBX implantation was performed (15). Kaplan-Meier survival curves were constructed for 7 days, at which time all surviving animals were euthanized.…”

“…The TBX trauma model is easy to execute and allows dose-dependent control of the degree of tissue injury. In our previous work, we showed that TBX induced systemic inflammation, vascular leakage and dose-dependent impairment of GI motility (15, 17). Heating and decellularisation of the TBX tissue with paracetic acid abrogated the effects on GI motility and elevation of serum cytokines and chemokines, demonstrating the presence and importance of living cells within the implant that drive these pathophysiological processes.…”

“…These studies show the increased lethality in combined injuries, more severe tissue damage and the importance of timing of the wounding for survival. Aforementioned combined injuries models, however, have not included sterile trauma with severe tissue damage to the muscle and bones as part of the combined injuries (15). The body’s response to different types of harmful impacts varies (16), and therefore, there is unmet need for an animal model of severe crush injury combined with radiation.…”

GABAA receptor overexpression in the lateral hypothalamic area attenuates gastric ischemia-reperfusion injury in rats

“…Major surgery-evoked ischemia has been demonstrated to induce gastric mucosal injury and gastrointestinal dysmotility (1,2). Previous studies (3)(4)(5) have shown that the hypothalamic paraventricular nucleus and the lateral hypothalamic area (LHA) are two specific hypothalamic nuclei that modulate gastric activity and gastric mucosal injury.…”