Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease

Summary

Principal Investigator: PAUL WESLEY NOBLE
Abstract: DESCRIPTION (provided by applicant): This Program Project Grant application will test the hypothesis that endogenous host factors generated in the context of either acute non-infectious lung injury or allergic inflammation play a fundamental role in the initiation and maintenance of inflammation and fibrosis associated with diseases such as pulmonary fibrosis and asthma. The collaborative studies that form the foundation of this proposal have shown that the extracellular matrix glycosaminoglycan hyaluronan (HA) is generated in the context of non-infectious acute lung injury and chronic inhaled allergen exposure. The overall hypothesis to be tested is that when unchecked, matrix fragments accumulating in the injured lung will propogate inflammation and facilitate an environment leading to the emergence of an invasive fibroblast phenotype that causes irreversible loss of lung function. Each project will probe different, yet complementary and sequencial processes of this proposed inflammatory cascade. Among the first wave of defense against excess inflammation are surfactant proteins. In the absence of SP-A and SP-D, HA fragment accumulation is augmented and both inflammation and fibrosis are more severe leading to irreversible loss of lung function. Project 2 (Wright) focuses on the mechanisms by which SP-A and SP-D interfere with matrix-driven inflammation and antagonize the functions of critical pro-fibrotic mediators such as TGF-beta. An important source of HA production are mesenchymal cells. When myofibroblasts are targeted to over-express hyaluronan synthase 2 (HAS2) in the mouse, a severe phenotype is generated leading to HA accumulation, unremitting inflammation and fibrodestructive lung disease with increased mortality. Project 1 (Noble) will determine the mechanisms by which HAS2 promotes airway remodeling and interstitial fibrosis using novel genetic models. Fibroblasts from asthmatic patients constitutively produce HA fragments and acquire an invasive phenotype in response to IL-13. Project 3 (Kraft) investigates the mechanisms by which HA and IL-13 regulate the development of the asthma phenotype in both man and mouse. Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases.
Funding Period: 2012-08-01 - 2017-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Pharmacotherapy of severe asthma
    Rafael Firszt
    Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
    Curr Opin Pharmacol 10:266-71. 2010
  2. pmc Obesity, metabolic dysregulation and oxidative stress in asthma
    Njira L Lugogo
    Department of Medicine, Duke University, Durham, NC, USA
    Biochim Biophys Acta 1810:1120-6. 2011

Research Grants

  1. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
  2. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
  3. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  4. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
  5. South Carolina IDeA Network of Biomedical Research Excellence
    LUCIA AMELIA PIRISI-CREEK; Fiscal Year: 2013
  6. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  7. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  9. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  10. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013

Detail Information

Publications3

  1. ncbi Pharmacotherapy of severe asthma
    Rafael Firszt
    Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
    Curr Opin Pharmacol 10:266-71. 2010
    ..Therefore, there is a crucial need to better understand the mechanisms and pathophysiology of severe asthma so more effective immunomodulators and biologic therapies can emerge...
  2. pmc Obesity, metabolic dysregulation and oxidative stress in asthma
    Njira L Lugogo
    Department of Medicine, Duke University, Durham, NC, USA
    Biochim Biophys Acta 1810:1120-6. 2011
    ..Epidemiological data demonstrate an increased risk of developing incident asthma with increasing adiposity. While the vast majority of studies support the interaction between obesity and asthma, the causality is unclear...

Research Grants30

  1. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  2. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  3. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  4. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  5. South Carolina IDeA Network of Biomedical Research Excellence
    LUCIA AMELIA PIRISI-CREEK; Fiscal Year: 2013
    ..We will intensify and focus our efforts to further build and support the pipeline for training, with particular attention to the recruitment and retention of minorities in biomedical science. ..
  6. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  7. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  9. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  10. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  11. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  12. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  13. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..