The contribution of prostanoids to allergy and lung inflammation Public Deposited

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  • March 22, 2019
Creator
  • Cote', Rachel Julia
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Through respiration, the airway is exposed to foreign materials and relies on the immune system to interpret each novel antigen's pathogenicity. Failure to establish unresponsiveness to innocuous particles can initiate atopy, characterized by elevated immunoglobulin E (IgE) levels. In susceptible individuals, asthma can develop, causing airway inflammation, reversible airflow obstruction, and airway hyperresponsiveness (AHR). Leukocytes rely on information received in the form of cytokines, chemokines, and lipid mediators to determine if an immune response is warranted or, alternatively, if immune tolerance should be established. Prostanoids are lipid mediators, produced by cyclooxygenase (COX) enzymes, which can both promote and limit inflammatory processes. Rodent models of atopic pulmonary allergy demonstrate that inhibition of prostanoid synthesis, by either COX isoform, augments disease parameters, assigning a protective role to these pathways. We evaluated the role of prostaglandin E2 (PGE2) to this process, utilizing mice lacking microsomal PGE2 synthase 1 (mPGES1). Unlike a loss of COX activity, a deficiency in mPGES1 ameliorates airway inflammation at a step subsequent to sensitization, suggesting that this prostanoid augments the effector arm of pulmonary allergy. Further, synthesis of PGE2 from the lung, itself, is implicated in our model. PGI2, another prostanoid, is thought to limit disease in multiple pulmonary afflictions. Utilizing IP -/- animals and COX-1 -/- animals, we demonstrate a contribution for this prostanoid in COX-1-dependent protection during atopic pulmonary episodes, potentially by inhibiting inflammatory cytokine release. While mediation by PGI2 occurs during both branches of an allergic response, the contribution is more substantial during allergy elicitation, perhaps indicating that local antigen exposure is a requirement for PGI2-mediated airway protection. Further we show that this protection occurs through immune cells recruited to the lung. Finally, we demonstrate that a loss of PGE2 or its receptors does not impede the immune system's ability to establish tolerance in the airways when innocuous antigen is inhaled prior to sensitization. Instead a modest reduction in tolerance is observed when PGI2 signaling through the IP receptor is lost. Taken together, the work presented in this dissertation suggests that PGI2, rather than PGE2, limits atopic immune responses in the respiratory tract.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology.
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  • Koller, Beverly H.
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