Targeting a Defined Surgical Stress-Induced Inflammatory Pathway to Improve Peri-Operative Outcomes

PROJECT SUMMARY/ ABSTRACT Despite improved intraoperative management some thoracic surgery patients suffer respiratory distress of unknown origin after lung resection. Based on human observational studies that eosinophilia in the perioperative period correlates with deleterious outcomes, we decided to study perioperative inflammation in a small animal model of lung surgery. We noted that pulmonary resection results in a transient but pronounced elevation of eosinophils in the blood and pulmonary tissue. Furthermore, we determined that global eosinophil depletion prior to lung resection substantially improves perioperative survival, oxygenation, and ameliorates post-operative pulmonary edema. The systemic increase in eosinophils results from their accelerated maturation from progenitors in the bone marrow. This process of maturation is, counterintuitively, accelerated by endogenous corticosteroids and is associated with the upregulation of specific cytokines in the bone marrow and lung tissue. Disruption of select cytokines, such as the alarmin IL-33, or genetic deletion of defined cell populations, such as innate lymphoid cells (ILCs), abrogates perioperative eosinophilia and improves animal survival after major pulmonary resection. These findings led to our central hypothesis that perioperative stress mediates endogenous steroid and cytokine-dependent eosinophil maturation and mobilization that is deleterious to recovery partially due to production of nitric oxide. To explore this hypothesis, we propose three Specific Aims. In Aim 1 we propose to define the mechanism/s of “stress-induced” endogenous corticosteroids that increase maturation of eosinophils after pulmonary resection. We will specifically focus on the cytokine environment as well as direct steroid sensitivity by eosinophils and their progenitors. In Aim 2 we will use cell- specific conditional gene knockout strains of mice to determine the mechanism/s of eosinophil recruitment and toxicity after pulmonary resection. We hypothesize IL-33 activates group 2 innate lymphoid cells (ILC2) which then promote eosinophil homing and/or maturation. We will also define the role of eosinophil produced nitric oxide in pulmonary pathology. In Aim 3 we will explore if excessive fluid administration and large ventilatory tidal volumes increase eosinophil maturation and/or toxicity. We also plan to evaluate if disruption of eosinophil development, by using clinically relevant protocols of IL-5 neutralization to effectively reduce their numbers, can ameliorate deleterious effects in the perioperative period. Our data will provide novel insight into cellular immune responses contributing to post-lung resection respiratory failure. Our data may allow for exploration of novel therapeutic strategies or repurposing of FDA-approved drugs not currently known to improve perioperative patient responses.