Alcohol and Impairment of the Granulopoietic Response to Pneumonia

Summary

Principal Investigator: Ping Zhang
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc 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
    Xin Shi
    Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
    Infect Immun 81:2197-205. 2013
  2. pmc Neonatal sepsis and neutrophil insufficiencies
    John Nicholas Melvan
    Department of Physiology and Alcohol Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
    Int Rev Immunol 29:315-48. 2010
  3. pmc Acute alcohol intoxication impairs the hematopoietic precursor cell response to pneumococcal pneumonia
    Caroline E Raasch
    Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112 1393, USA
    Alcohol Clin Exp Res 34:2035-43. 2010
  4. pmc Thymopoietic and bone marrow response to murine Pneumocystis pneumonia
    Xin Shi
    Section of Pulmonary Critical Care Medicine, Department of Medicine, LSU Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, USA
    Infect Immun 79:2031-42. 2011
  5. pmc Alcohol suppresses the granulopoietic response to pulmonary Streptococcus pneumoniae infection with enhancement of STAT3 signaling
    Robert W Siggins
    Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    J Immunol 186:4306-13. 2011
  6. pmc Suppression of the stem cell antigen-1 response and granulocyte lineage expansion by alcohol during septicemia
    John N Melvan
    Departments of Physiology, Section of Pulmonary Critical Care Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
    Crit Care Med 39:2121-30. 2011
  7. pmc Alcohol impairs the myeloid proliferative response to bacteremia in mice by inhibiting the stem cell antigen-1/ERK pathway
    John Nicholas Melvan
    Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    J Immunol 188:1961-9. 2012

Detail Information

Publications7

  1. pmc 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
    Xin Shi
    Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
    Infect Immun 81:2197-205. 2013
    ..These results demonstrate that TLR4/Sca-1 signaling plays an important role in the regulation of hematopoietic precursor cell programming and their enhancement of granulocyte lineage commitment in response to E. coli bacteremia...
  2. pmc Neonatal sepsis and neutrophil insufficiencies
    John Nicholas Melvan
    Department of Physiology and Alcohol Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
    Int Rev Immunol 29:315-48. 2010
    ..This article reviews current strategies for the clinical management of neonatal sepsis and analyzes mechanisms underlying insufficiencies of neutrophil defense in neonates with emphasis on new directions for adjuvant therapy development...
  3. pmc Acute alcohol intoxication impairs the hematopoietic precursor cell response to pneumococcal pneumonia
    Caroline E Raasch
    Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112 1393, USA
    Alcohol Clin Exp Res 34:2035-43. 2010
    ..Alcoholic patients with pneumonia frequently present with granulocytopenia, which is predictive of increased mortality. The mechanisms underlying this impaired granulopoietic response to pneumococcal pneumonia have yet to be elucidated...
  4. pmc Thymopoietic and bone marrow response to murine Pneumocystis pneumonia
    Xin Shi
    Section of Pulmonary Critical Care Medicine, Department of Medicine, LSU Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, USA
    Infect Immun 79:2031-42. 2011
    ....
  5. pmc Alcohol suppresses the granulopoietic response to pulmonary Streptococcus pneumoniae infection with enhancement of STAT3 signaling
    Robert W Siggins
    Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    J Immunol 186:4306-13. 2011
    ....
  6. pmc Suppression of the stem cell antigen-1 response and granulocyte lineage expansion by alcohol during septicemia
    John N Melvan
    Departments of Physiology, Section of Pulmonary Critical Care Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
    Crit Care Med 39:2121-30. 2011
    ..This study investigated the involvement of stem cell antigen-1 expression by granulocyte lineage-committed progenitors in the granulopoietic response to septicemia and how alcohol affected this response...
  7. pmc Alcohol impairs the myeloid proliferative response to bacteremia in mice by inhibiting the stem cell antigen-1/ERK pathway
    John Nicholas Melvan
    Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    J Immunol 188:1961-9. 2012
    ..Suppression of this response could represent an underlying mechanism for developing myelosuppression in alcohol-abusing hosts with severe bacterial infection...