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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Fattahi, Fatemeh; Kalbitz, Miriam; Malan, Elizabeth A et al. (2017) Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction. FASEB J 31:4129-4139
Fattahi, Fatemeh; Grailer, Jamison J; Lu, Hope et al. (2017) Selective Biological Responses of Phagocytes and Lungs to Purified Histones. J Innate Immun 9:300-317
Fattahi, Fatemeh; Ward, Peter A (2017) Complement and sepsis-induced heart dysfunction. Mol Immunol 84:57-64
Kalbitz, Miriam; Fattahi, Fatemeh; Herron, Todd J et al. (2016) Complement Destabilizes Cardiomyocyte Function In Vivo after Polymicrobial Sepsis and In Vitro. J Immunol 197:2353-61
Fattahi, Fatemeh; Ward, Peter A (2016) Anti-inflammatory interventions-what has worked, not worked, and what may work in the future. Transl Res 167:1-6
Delano, Matthew J; Ward, Peter A (2016) The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev 274:330-353
Standiford, Theodore J; Ward, Peter A (2016) Therapeutic targeting of acute lung injury and acute respiratory distress syndrome. Transl Res 167:183-91
Kalbitz, Miriam; Fattahi, Fatemeh; Grailer, Jamison J et al. (2016) Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis. FASEB J 30:3997-4006
Haggadone, Mikel D; Grailer, Jamison J; Fattahi, Fatemeh et al. (2016) Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes. Mediators Inflamm 2016:1340156
Delano, Matthew J; Ward, Peter A (2016) Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 126:23-31

Showing the most recent 10 out of 67 publications