Pneumonia is a leading cause of infectious death in the United States. Alcohol predisposes the host to bacterial infections, particularly pneumonia. Alcohol abusing patients with pneumonia frequently present with granulocytopenia, which is an indicator of increased mortality. The mechanisms by which alcohol injures the marrow granulopoietic response to lung infection remain unclear. During pulmonary infection, the production of granulocyte colony-stimulating factor (G-CSF) by infected tissue is significantly increased. G-CSF is an essential granulopoietic cytokine that stimulates myeloid progenitor cell proliferation and granulocyte production in bone marrow. Binding of G-CSF to its receptor activates the p44/42-cyclin D pathway to promote myeloid progenitor cell proliferation. G-CSF also activates signal transducer and activator of transcription 3 (STAT3)-cyclin-dependent kinase (CDK) inhibitor p27Kip1 pathway that provides a negative feedback signal to cause G1 cell cycle arrest. Our preliminary data show that alcohol suppresses granulopoietic progenitor cell proliferation in response to pneumococcal pneumonia or G-CSF stimulation. Alcohol inhibits G-CSF-induced activation of the p44/42-cyclin D pathway while it enhances STAT3- p27Kip1 negative signaling. In this project, we will investigate the cell signaling mechanisms by which alcohol impairs the granulopoietic response to bacterial pneumonia. Our hypothesis is that alcohol suppresses the granulopoietic response to pneumococcal pneumonia by impairing G-CSF signaling in myeloid progenitor cells. The proposed two specific aims are: 1) To test the hypothesis that alcohol inhibits the granulopoietic response to lung infection by inhibiting G-CSF-induced activation of the p44/42-cyclin D pathway in granulopoietic cells;2) To test the hypothesis that alcohol impairs myeloid progenitor cell proliferation in response to G-CSF by enhancing the STAT3-p27Kip1 negative feedback pathway. The direct effects of alcohol versus indirect effects of oxidative stress generated from alcohol metabolism on both branches of G-CSF signaling will also be studied. This investigation will provide novel information focused on the pathogenesis of granulocytopenia in alcohol abusers with serious infections. It may also identify potential therapeutic approaches for the effective treatment of pneumonia in these immunocompromised patients.
Alcohol abuse predisposes the host to pneumonia which is a leading cause of infectious death in the United States. Many alcoholic patients with pneumonia present with leukopenia, which is frequently fatal. This project investigates the mechanisms underlying this serious health problem and will help to identify therapeutic approaches for effective treatment of alcoholic patients with severe lung infection.
|Shi, Xin; Siggins, Robert W; Stanford, William L et al. (2013) Toll-like receptor 4/stem cell antigen 1 signaling promotes hematopoietic precursor cell commitment to granulocyte development during the granulopoietic response to Escherichia coli bacteremia. Infect Immun 81:2197-205|
|Melvan, John Nicholas; Siggins, Robert W; Stanford, William L et al. (2012) Alcohol impairs the myeloid proliferative response to bacteremia in mice by inhibiting the stem cell antigen-1/ERK pathway. J Immunol 188:1961-9|
|Melvan, John N; Siggins, Robert W; Bagby, Gregory J et al. (2011) Suppression of the stem cell antigen-1 response and granulocyte lineage expansion by alcohol during septicemia. Crit Care Med 39:2121-30|
|Shi, Xin; Zhang, Ping; Sempowski, Gregory D et al. (2011) Thymopoietic and bone marrow response to murine Pneumocystis pneumonia. Infect Immun 79:2031-42|
|Siggins, Robert W; Melvan, John N; Welsh, David A et al. (2011) Alcohol suppresses the granulopoietic response to pulmonary Streptococcus pneumoniae infection with enhancement of STAT3 signaling. J Immunol 186:4306-13|
|Raasch, Caroline E; Zhang, Ping; Siggins 2nd, Robert W et al. (2010) Acute alcohol intoxication impairs the hematopoietic precursor cell response to pneumococcal pneumonia. Alcohol Clin Exp Res 34:2035-43|
|Melvan, John Nicholas; Bagby, Gregory J; Welsh, David A et al. (2010) Neonatal sepsis and neutrophil insufficiencies. Int Rev Immunol 29:315-48|