These studies will evaluate the role of the adrenergic system in regulation of the acute inflammatory response, especially in the setting of acute lung injury (ALI).
In Aim 1, we will evaluate lung dendritic cells (DCs), lung macrophages and alveolar epithelial cells (AECs) for the presence of a2 adrenergic receptors (a2A, a2B, a2C) as well as inducible catecholamine synthases and hydrolases, and how these receptors and enzymes affect cell responses to C5a, LPS, or both.
In Aim 2, we will evaluate adrenergic regulation of the local inflammatory response (ALI following pulmonary deposition of LPS or IgG immune complexes) and the systemic inflammatory response (""""""""cytokine storm"""""""" following cecal ligation and puncture, CLP).
In Aim 3, we will evaluate the three cell types (described above) for their ability to respond to C5a or LPS, or both, resulting in enhanced cytokine responses via epigenetic changes occurring in these cells.
In Aim 4, we will assess the role of ?2AR agonists in ALI, pursuing preliminary evidence that ALI, following intrapulmonary deposition of LPS or IgGICs, is greatly attenuated by the presence of specific isomeric forms of albuterol and formoterol. We will assess the molecular mechanisms for the protective effects of 22AR agonists, including effects on signaling pathways. Collectively, these studies should demonstrate how the adrenergic system regulates the acute inflammatory response, especially in the lung.
Acute lung inflammation involving the upper airways (as in asthma, COPD, cystic fibrosis) or the lower airways (as in acute lung injury [ALI] or acute respiratory distress syndrome [ARDS]) affects millions of individuals in North America, resulting in high morbidity and mortality. The mechanisms of these lung inflammatory disorders are poorly understood. The proposed work will relate to our recent discoveries that the adrenergic nervous system plays an important role in acute lung inflammation and can be manipulated for therapeutic benefit.
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