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Abstract: TH-PO548

Afferent but Not Efferent Vagus Nerve Stimulation Reduces Endotoxin-Induced Acute Lung Injury via Vagosympathetic Communication

Session Information

  • Pathology and Lab Medicine
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

  • 1700 Pathology and Lab Medicine

Authors

  • Poudel, Nabin, UVA Health, Charlottesville, Virginia, United States
  • Kuwabara, Shuhei, UVA Health, Charlottesville, Virginia, United States
  • Tanaka, Shinji, UVA Health, Charlottesville, Virginia, United States
  • Goggins, Eibhlin S,, UVA Health, Charlottesville, Virginia, United States
  • Okusa, Mark D., UVA Health, Charlottesville, Virginia, United States
Background

Vagus nerve stimulation (VNS) has a potent anti-inflammatory effect during inflammatory conditions such as acute kidney injury (AKI), arthritis, and experimental sepsis. Sepsis is an acute life-threatening condition that results from hyperactivation of the immune system as a response to infection and involves injury to multiple organs such as kidneys and lungs. We previously showed that VNS is protective in ischemia reperfusion injury induced AKI. We hypothesized that VNS protects mice from sepsis induced acute lung injury (ALI).

Methods

VNS was performed by exposing the left cervical vagus nerve (VN) and stimulating either electrically (eVNS) in C57BL/6 mice or optogenetically (optoVNS) in transgenic mice expressing channelrhodopsin-2 specifically in either afferent or efferent VN. Unidirectional selective VNS was performed by applying bupivacaine to one end of VN followed by VNS. Local sympathetic denervation was achieved by intranasal instillation of 6-hydroxydopamine. Hypothalamo-pituitary-adrenocortical (HPA) axis was blocked using mifepristone. 24 hours after VNS, animals were instilled with lipopolysaccharide intranasally to induce ALI followed by analysis of bronchoalveolar lavage (BAL) and lung tissues at 6 hours. Flow cytometry was performed to quantify immune cell infiltration. Luminex was performed to quantify cytokine levels. H&E staining was performed to evaluate extent of lung injury.

Results

We observed a significant reduction in immune cell infiltration in the alveolar space after eVNS. Selective central eVNS to stimulate afferent VN also reduced LPS induced leukocyte counts in the BAL, while selective distal eVNS failed to exert this effect. Moreover, optoVNS of anterograde afferent VN ameliorated lung injury which was abrogated by local sympathetic denervation of the lung and airway. Blocking the HPA axis did not alter the protective effect of VNS. Cytokine analysis showed that afferent VNS decreased pro-inflammatory cytokines Cxcl1, Cxcl10, RANTES, and Vegfa.

Conclusion

Our previous and current data collectively suggest that VNS can be an effective therapeutic approach for acute inflammatory conditions such as AKI and ALI. This phenotype is mediated by reduced cytokine production and an overall reduction in inflammatory cells recruitment in the target organ.

Funding

  • NIDDK Support