Wednesday, December 4, 2024
12/4/2024
Abstract It is now widely appreciated that uncontrolled inflammation is a unifying component in many widespread diseases, including chronic lung disease. Inhalational exposure to respirable particulate matter can be an important precipitant or exacerbant of lung inflammation. From our earlier results, the resolution of inflammation is known today as an active process. There are several new families of specialized pro-resolving mediators (SPMs) identified and characterized in acute inflammation. These protective mediators are enzymatically produced and are agonists at specific receptors transducing cell type specific functional responses critical in tissue resolution. Resolution programs of the inflammatory response are essentially uncharted scientific terrain in environmental health and medicine. Fundamental information is critically needed on the impact of environmental agents within the resolution response and whether they perturb resolution to trigger chronic inflammatory responses and susceptibility to allergen induced asthma. Here, the laboratories of Bruce Levy, Charles Serhan, Phil Demokritou, and Adam Haber collaborate and propose an innovative proposal focusing on elucidating the impact of inhaled potentially hazardous traffic emitted ultrafine particles (UFPs) on the new resolution programs that govern pro-resolving cellular and molecular mechanisms and tissue catabasis in its return to homeostasis. Failed resolution or its disruption can lead to sustained lung inflammation and enhanced susceptibility to allergen induced asthma. This proposal will test an innovative hypothesis, namely that exposure to traffic-emitted UFPs disrupts airway resolution mechanisms associated with allergic airway responses in part via changes in specialized pro-resolving mediator production and action; and that delivering SPMs using a novel nanocarrier platform can protect from UFP-initiated disruption of endogenous resolution mechanisms. To test this hypothesis, an interdisciplinary team of scientists was assembled with expertise in environmental health and particle health effect studies (Demokritou), computational biology (Haber), asthma, lung inflammation and its resolution (Levy) and SPMs, SPM receptors and resolution (Serhan) to pursue the following specific aims: Aim 1. Collect and physicochemically characterize traffic emitted UFPs in urban Boston, Aim 2. Determine the impact of traffic emitted UFPs on the resolution of house dust mite (HDM) evoked allergic airway responses, and Aim 3. Determine the cellular and molecular mechanisms for UFP disrupted resolution of inflammation and establish an SPM delivery system to activate catabasis. These innovative and timely studies will establish the impact of environmental UFPs on endogenous resolution programs in lung inflammation and lay the groundwork for new therapeutic approaches with resolution agonists that promote active resolution of inflammation in our fight against environmental insults.
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