Precision targeting of the vagal anti-inflammatory pathway attenuates the systemic inflammatory response to burn injury

Abstract

BACKGROUND:The systemic inflammatory response (SIRS) drives late morbidity and mortality after injury. The α7 nicotinic acetylcholine receptor (α7nAchR) expressed on immune cells regulates the vagal anti-inflammatory pathway that prevents an overwhelming SIRS response to injury. Nonspecific pharmacologic stimulation of the vagus nerve has been evaluated as a potential therapeutic to limit SIRS. Unfortunately, the results of clinical trials have been underwhelming. We hypothesized that directly targeting the α7nAchR would more precisely stimulate the vagal anti-inflammatory pathway on immune cells and decrease gut and lung injury after severe burn. METHODS:C57BL/6 mice underwent 30% total body surface area steam burn. Mice were treated with an intraperitoneal injection of a selective agonist of the α7nAchR (AR-R17779) at 30 minutes postburn. Intestinal permeability to 4 kDa FITC-dextran was measured at multiple time points postinjury. Lung vascular permeability was measured 6 hours after burn injury. Serial behavioral assessments were performed to quantify activity levels. RESULTS:Intestinal permeability peaked at 6 hours postburn. AR-R17779 decreased burn-induced intestinal permeability in a dose-dependent fashion ( p < 0.001). There was no difference in gut permeability to 4 kDa FITC-dextran between sham and burn-injured animals treated with 5 mg/kg of AR-R17779. While burn injury increased lung permeability 10-fold, AR-R17779 prevented burn-induced lung permeability with no difference compared with sham ( p < 0.01). Postinjury activity levels were significantly improved in burned animals treated with AR-R17779. CONCLUSION: Directly stimulating the α7nAchR prevents burn-induced gut and lung injury. Directly targeting the α7nAChR that mediates the cholinergic anti-inflammatory response may be an improved strategy compared with nonspecific vagal agonists.

A Heterogenous Population of Extracellular Vesicles Mobilize to the Alveoli Post-Injury

“…We found that EVs expressing CD44 increased in the early time points in a burn model that we have previously shown is associated with ALI. 12,13,16 CD44 is a transmembrane adhesion molecule expressed on several cell types, including leukocytes. It contributes to the innate immune response to injury through monocyte proliferation, phagocytosis, and CD44 ligand hyaluronic acid clearance.…”

“…The dorsal fur of the mouse was clipped with an electronic hair clipper prior to a 7-second steam burn on the dorsal skin using a template that estimates 30% total body surface area burn that is associated with ALI as previously described. 13,16 Following injury, animals received fluid resuscitation with 1.5 ml of 0.9% normal saline SQ and were placed in their respective cages on a warming pad to recover. Sham mice underwent general anesthesia, fur clipping, injection of buprenorphine and normal saline but were not burned.…”

“…We have previously shown that this burn injury model leads to SIRS that affects the lungs within 4 hours. 13,16 Therefore, BAL was collected 4 hours postinjury from burn versus sham mice, and EV separated from cells by serial centrifugation and the EVs purified by SEC (Fig. 1A).…”

Neuromodulation Strategies to Reduce Inflammation and Improve Lung Complications in COVID-19 Patients

“…Electrical VNS was first shown to protect against excessive inflammation in 2000, when Borovikova et al reported that VNS reduces systemic proinflammatory cytokine production and maintains blood pressure in a rodent model of endotoxic shock (22). Electrically or pharmacologically stimulating the CAP protects against excessive systemic inflammation, maintains tissue perfusion, and preserves vital organ function in models of arthritis, burns, colitis, hemorrhagic shock, polymicrobial intraabdominal sepsis, and stroke (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Importantly, disruption of CAP signaling delays resolution of inflammation and bacterial clearance in experimental peritonitis (35).…”

Exosomes and Their Bioengineering Strategies in the Cutaneous Wound Healing and Related Complications: Current Knowledge and Future Perspectives

“…The difficulty lies in treating severe trauma and its complications. Because of the lack of a skin barrier system, severe trauma patients often risk sepsis/systemic inflammatory response syndrome (SIRS)/cytokine storm due to infection 228 , 229 . If the infection worsens, patients will likely die from multiple organ dysfunction syndromes 230 .…”