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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029507-31
Application #
8535776
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dunsmore, Sarah
Project Start
1982-07-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
31
Fiscal Year
2013
Total Cost
$298,608
Indirect Cost
$97,984
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Grailer, Jamison J; Fattahi, Fatemeh; Dick, Rachel S et al. (2015) Cutting edge: critical role for C5aRs in the development of septic lymphopenia in mice. J Immunol 194:868-72
Bosmann, Markus; Russkamp, Norman F; Strobl, Birgit et al. (2014) Interruption of macrophage-derived IL-27(p28) production by IL-10 during sepsis requires STAT3 but not SOCS3. J Immunol 193:5668-77
Grailer, Jamison J; Kalbitz, Miriam; Zetoune, Firas S et al. (2014) Persistent neutrophil dysfunction and suppression of acute lung injury in mice following cecal ligation and puncture sepsis. J Innate Immun 6:695-705
Bosmann, Markus; Ward, Peter A (2014) Protein-based therapies for acute lung injury: targeting neutrophil extracellular traps. Expert Opin Ther Targets 18:703-14
Grailer, Jamison J; Haggadone, Mikel D; Sarma, J Vidya et al. (2014) Induction of M2 regulatory macrophages through the ?2-adrenergic receptor with protection during endotoxemia and acute lung injury. J Innate Immun 6:607-18
Grailer, Jamison J; Canning, Bethany A; Kalbitz, Miriam et al. (2014) Critical role for the NLRP3 inflammasome during acute lung injury. J Immunol 192:5974-83
Bosmann, Markus; Meta, Fabien; Ruemmler, Robert et al. (2013) Regulation of IL-17 family members by adrenal hormones during experimental sepsis in mice. Am J Pathol 182:1124-30
Perlman, Harris; Budinger, G R Scott; Ward, Peter A (2013) Humanizing the mouse: in defense of murine models of critical illness. Am J Respir Crit Care Med 187:898-900
Bosmann, Markus; Haggadone, Mikel D; Zetoune, Firas S et al. (2013) The interaction between C5a and both C5aR and C5L2 receptors is required for production of G-CSF during acute inflammation. Eur J Immunol 43:1907-13
Bosmann, Markus; Ward, Peter A (2013) The inflammatory response in sepsis. Trends Immunol 34:129-36

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