Specialty Areas: Host Defense Mechanisms in the Lungs, Bacterial Pneumonia, Acute Lung Injury/Acute Respiratory Distress Syndrome, Cigarette- Induced Lung Disease
Dr. Doerschuk’s research addresses host defense mechanisms in the lungs, particularly the inflammatory and innate immune processes that are important in the pathogenesis and course of bacterial pneumonia, acute lung injury/acute respiratory distress syndrome, and cigarette-smoke induced lung disease. Basic and translational studies address the mechanisms of host defense, including leukocyte recruitment, edema, bacterial clearance and lung injury/resolution. Although these processes are important in all inflammatory lung diseases, her work particularly addresses pneumonia and the acute respiratory distress syndrome using in vivo, translational, cell biological, immunological, and molecular approaches. These studies investigate pathogens that cause community-acquired and nosocomial pneumonias occurring in immunocompromised patients, including those with cancer. Her ultimate goal is to use this knowledge to develop therapies that enhance the inflammatory response when it is beneficial to the host and dampen this response when it is harmful.
Leukocytes circulating in the blood stream are recruited to the site of infection in the lungs early in the inflammatory process. Studies address the mechanisms through which the lungs produce cytokines, chemokines and other regulatory inflammatory mediators in response to bacteria or other stimuli that then induce the production of other mediators and adhesion molecules on endothelial cells and result in the recruitment of leukocytes. Current studies address how leukocytes recognize sites of infection and how these mediators induce changes in the adhesivity and mechanical properties of neutrophils, usually the earliest leukocyte to respond and accumulate in the lungs.
The pulmonary microvascular endothelial cells have unique properties that regulate both fluid flux within the lungs and the migration of neutrophils from the blood stream into the lung tissue. These cells, along with epithelial cells within the airways and the airspaces, tightly regulate lung permeability and maintain a delicate balance of fluid flux. Major areas of study include the biology of adhesion molecules, including both their expression and function on endothelial cells and leukocytes. For example, ongoing studies determine the intracellular signaling pathways initiated by the ligation of the adhesion molecules ICAM-1 and E-selectin by their receptors on neutrophils and how these signaling pathways regulate transendothelial migration of neutrophils and fluid permeability. Other studies address the function of Rho GTPases, particularly Rac2, which she showed is expressed in endothelial cells and regulates both normal fluid flux and edema formation during injury.
Cigarette smoke induces lung injuries, including chronic obstructive pulmonary disease (COPD), both emphysema and chronic bronchitis, and lung cancer. Studies pursue the mechanisms through which cigarette smoke induces inflammatory and neoplastic processes that result in these diseases.
Once leukocytes are recruited to the infection or other injury, they have many functions in resolving the infection. Neutrophils are important in clearing the bacteria and repairing any tissue damage. The mechanisms through which this is accomplished are an active area of study. For example, neutrophils have recently been shown to produce interferon-γ early in the course of some pneumonias through a very tightly regulated process that likely involves microRNAs. How the production of this molecule is regulated, its role in host defense, and the potential of this molecule as an important therapy in modulating host defense in immunocompromised patients are active areas of study.
Dr. Doerschuk heads the new Center for Airways Disease. The Center’s goal is to further our conceptual and mechanistic understanding of diseases that affect the airways of the lungs, particularly smoking-related diseases such as chronic obstructive pulmonary disease and lung cancer, as well as lung infections, including pneumonia. The Center’s mission is to stimulate research that defines airways disease at a molecular level, enabling early diagnosis, prognosis and personalized treatment of patients with these lung diseases. The ultimate goal is to translate research findings into better care for residents of North Carolina and throughout the nation, addressing both the disease predictors and therapies and the social and behavioral aspects of these diseases.
- Moore SM, Zhang H, Maeda N, Doerschuk CM, Faber JE. Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury. Angiogenesis. 2015 Jul;18(3):265-81. doi: 10.1007/s10456-015-9465-6. Epub 2015 Apr 11. PubMed PMID: 25862671; PubMed Central PMCID: PMC4475464.
- Saini Y, Wilkinson KJ, Terrell KA, Burns KA, Livraghi-Butrico A, Doerschuk CM, O’Neal WK, Boucher RC. Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses. Am J Respir Cell Mol Biol. 2015 Jun 29. [Epub ahead of print] PubMed PMID: 26121027.
- Gomez JC, Yamada M, Martin JR, Dang H, Brickey WJ, Bergmeier W, Dinauer MC, Doerschuk CM. Mechanisms of interferon-γ production by neutrophils and its function during Streptococcus pneumoniae pneumonia. Am J Respir Cell Mol Biol. 2015 Mar;52(3):349-64. doi: 10.1165/rcmb.2013-0316OC. PubMed PMID: 25100610; PubMed Central PMCID: PMC4370257.
- Doerschuk CM. Pulmonary alveolar proteinosis and macrophage transplantation. N Engl J Med. 2015 Apr 30;372(18):1762-4. doi: 10.1056/NEJMcibr1413035. PubMed PMID: 25923557.
- Freeman CM, Crudgington S, Stolberg VR, Brown JP, Sonstein J, Alexis NE, Doerschuk CM, Basta PV, Carretta EE, Couper DJ, Hastie AT, Kaner RJ, O’Neal WK, Paine R 3rd, Rennard SI, Shimbo D, Woodruff PG, Zeidler M, Curtis JL. Design of a multi-center immunophenotyping analysis of peripheral blood, sputum and bronchoalveolar lavage fluid in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). J Transl Med. 2015 Jan 27;13:19. doi: 10.1186/s12967-014-0374-z. PubMed PMID: 25622723; PubMed Central PMCID: PMC4314767.
- O’Neal WK, Anderson W, Basta PV, Carretta EE, Doerschuk CM, Barr RG, Bleecker ER, Christenson SA, Curtis JL, Han MK, Hansel NN, Kanner RE, Kleerup EC, Martinez FJ, Miller BE, Peters SP, Rennard SI, Scholand MB, Tal-Singer R, Woodruff PG, Couper DJ, Davis SM; SPIROMICS Investigators. Comparison of serum, EDTA plasma and P100 plasma for luminex-based biomarker multiplex assays in patients with chronic obstructive pulmonary disease in the SPIROMICS study. J Transl Med. 2014 Jan 8;12:9. doi: 10.1186/1479-5876-12-9. PubMed PMID: 24397870; PubMed Central PMCID: PMC3928911.