CHANGES IN INSULIN RESISTANCE ASSOCIATED WITH CHRONIC AIRWAY ALLERGEN EXPOSURES IN A SPONTANEOUSLY OBESE, NONHUMAN PRIMATE MODEL OF ALLERGIC ASTHMA

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Hannah G Woolard (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Obesity and asthma are two major well-recognized and interconnected major health problems, but the mechanisms that underlie the association of these two chronic inflammatory disease states are still unknown. Novel insights including the central role of inflammation and metabolic dysfunction, have been reported but even more complexity has arisen by the many co-morbidities common to both obesity and asthma. Of particular interest is the role of insulin resistance, which has been heavily implicated as the possible missing link required for understanding the etiology and underlying pathophysiological mechanisms resulting in a more severe, difficult to treat asthma. Hence, the proposed research project presented in this thesis was conducted to specifically investigate the relationship/interaction/association between the development of insulin resistance (induced by obesity) and allergen-induced allergic asthma. From an established non-human primate model of allergic asthma, we studied a cohort of obese, male 10-year-old rhesus macaques with varying historical degrees of airway hyperreactivity and changes in insulin resistance. We hypothesized chronic aero-HDM exposures would induce increased airway hyperreactivity and pulmonary inflammation which would be associated with the worsening development of insulin resistance. To test this hypothesis, we paired animals according to historical AHR, then exposed one animal from each pair to aero-HDM and the other to aero-saline/SHAM, monthly for 6 months. We assessed body composition, insulin resistance via intravenous glucose tolerance test, the early asthmatic response AHR to aero-HDM/saline, as well as the late asthmatic response AHR to aero-Mch and pulmonary inflammation via bronchoalveolar lavage. We found increased AHR to aero-HDM coincident with eosinophil-dominate pulmonary inflammation for all five HDM-exposed study animals, mirroring the early-onset, eosinophilic obese asthma endotype. SHAM-exposed animals did not manifest increases in AHR to aero-saline nor aero-Mch, yet two animals manifested increased eosinophilic pulmonary inflammation (similar to HDM-exposed animals) and interesting one animal manifested neutrophilic inflammation mirroring the non-eosinophilic, neutrophil-dominant inflammatory endotype reported in the literature for the late-onset, non-atopic obese asthma phenotype. Due to high variability and limited time points, no significant changes were observed for the IR indices however an interesting negative trend between changes in AHR and HOMA-IR, an index of insulin resistance, was observed for 3/5 HDM-exposed animals suggesting increased AHR was associated with decreased HOMA-IR/improved IR, not supporting our original hypothesis. Further studies identifying and understanding the unique inflammatory biomarkers and mechanisms linking allergic asthma, obesity, insulin resistance, and related sequalae are necessary for targeted therapeutic development and the proper treatment of the heterogeneous nature of obesity associated asthma and the inevitable metabolic consequences.

Additional Information

Publication

Thesis

Language: English

Date: 2023

Subjects

nonhuman primate

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