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.
Neutrophil adherence induces an increase in the phosphorylated p38 MAPK in TNF-α-pretreated pulmonary microvascular endothelial cells. The distribution of phosphorylated p38 (green) and F-actin (red) in ECs without neutrophils or with neutrophils adherent for 2 or 6 min was examined using confocal microscopy. A representative image through a slice of ECs is shown, and the arrows indicate the position of adherent neutrophils. Quantification of many images revealed that the number of pixels showing bright staining for phosphorylated p38 MAPK increased in endothelial cells at 2 and 6 minutes of neutrophil adherence. Wang Q et al., AJP Lung Cell Mol Biol288:L359-369, 2005
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.
- Anderson WH, Ha JW, Couper DJ, O’Neal WK, Barr RG, Bleecker ER, Carretta EE, Cooper CB, Doerschuk CM, Drummond MB, Han MK, Hansel NN, Kim V, Kleerup EC, Martinez FJ, Rennard SI, Tashkin D, Woodruff PG, Paine R 3rd, Curtis JL, Kanner RE; SPIROMICS Research Group. Variability in objective and subjective measures affects baseline values in studies of patients with COPD. PLoS One. 2017 Sep 21;12(9):e0184606. doi: 10.1371/journal.pone.0184606. eCollection 2017. PMID: 28934249.
- Gomez JC, Dang H, Kanke M, Hagan RS, Mock JR, Kelada SNP, Sethupathy P, Doerschuk CM. Predicted effects of observed changes in the mRNA and microRNA transcriptome of lung neutrophils during S. pneumoniae pneumonia in mice. Sci Rep. 2017 Sep 12;7(1):11258. doi: 10.1038/s41598-017-11638-7. PMID: 28900269; PMCID: PMC5595893.
- Martinez CH, Li SX, Hirzel AJ, Stolberg VR, Alexis NE, Barr RG, Bleecker ER, Carretta EE, Christenson SA, Cooper CB, Couper DJ, Doerschuk CM, Han MK, Hansel NN, Hastie AT, Hoffman EA, Kaner RJ, Martinez FJ, Meyers DA, O’Neal WK, Paine R 3rd, Putcha N, Rennard SI, Woodruff PG, Zeidler M, Curtis JL, Freeman CM; SPIROMICS Investigators. Alveolar eosinophilia in current smokers with chronic obstructive pulmonary disease in the SPIROMICS cohort. J Allergy Clin Immunol. 2017 Sep 12. doi: 10.1016/j.jaci.2017.07.039. [Epub ahead of print] PMID: 28916185.
- Kesimer M, Ford AA, Ceppe A, Radicioni G, Cao R, Davis CW, Doerschuk CM, Alexis NE, Anderson WH, Henderson AG, Barr RG, Bleecker ER, Christenson SA, Cooper CB, Han MK, Hansel NN, Hastie AT, Hoffman EA, Kanner RE, Martinez F, Paine R 3rd, Woodruff PG, O’Neal WK, Boucher RC. Airway mucin concentration as a marker of chronic bronchitis. N Engl J Med. 2017 Sep 7;377(10):911-922. doi: 10.1056/NEJMoa1701632. PMID: 28877023.
- Schick SF, Blount BC, Jacob P Rd, Saliba NA, Bernert JT, El Hellani A, Jatlow P, Pappas RS, Wang L, Foulds J, Ghosh A, Hecht SS, Gomez JC, Martin JR, Mesaros C, Srivastava S, St Helen G, Tarran R, Lorkiewicz PK, Blair IA, Kimmel HL, Doerschuk CM, Benowitz NL, Bhatnagar A. Biomarkers of exposure to new and emerging tobacco delivery products. Am J Physiol Lung Cell Mol Physiol. 2017 Sep 1;313(3):L425-L452. doi: 10.1152/ajplung.00343.2016. Epub 2017 May 18. Review. PMID: 28522563.
- Dial CF, Tune MK, Doerschuk CM, Mock JR. Foxp3+ regulatory T cell expression of keratinocyte growth factor enhances lung epithelial proliferation. Am J Respir Cell Mol Biol. 2017 Aug;57(2):162-173. doi: 10.1165/rcmb.2017-0019OC. PMID: 28296468.
- Han MK, Quibrera PM, Carretta EE, Barr RG, Bleecker ER, Bowler RP, Cooper CB, Comellas A, Couper DJ, Curtis JL, Criner G, Dransfield MT, Hansel NN, Hoffman EA, Kanner RE, Krishnan JA, Martinez CH, Pirozzi CB, O’Neal WK, Rennard S, Tashkin DP, Wedzicha JA, Woodruff P, Paine R 3rd, Martinez FJ; SPIROMICS Investigators. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2017 Aug;5(8):619-626. doi: 10.1016/S2213-2600(17)30207-2. Epub 2017 Jun 28. PMID: 28668356.
- Gomez JC, Doerschuk CM. Activating integrins isn’t always “beta” for neutrophil migration! Am J Respir Cell Mol Biol. 2017 May;56(5):561-562. doi: 10.1165/rcmb.2017-0066ED. PMID: 28459388.
- Esther CR Jr, Hill DB, Button B, Shi S, Jania C, Duncan EA, Doerschuk CM, Chen G, Ranganathan S, Stick SM, Boucher RC. Sialic acid-to-urea ratio as a measure of airway surface hydration. Am J Physiol Lung Cell Mol Physiol. 2017 Mar 1;312(3):L398-L404. doi: 10.1152/ajplung.00398.2016. Epub 2017 Jan 6. PMID: 28062483.
- Keene JD, Jacobson S, Kechris K, Kinney GL, Foreman MG, Doerschuk CM, Make BJ, Curtis JL, Rennard SI, Barr RG, Bleecker ER, Kanner RE, Kleerup EC, Hansel NN, Woodruff PG, Han MK, Paine R 3rd, Martinez FJ, Bowler RP, O’Neal WK; COPDGene and SPIROMICS Investigators. Biomarkers predictive of exacerbations in the SPIROMICS and COPDGene Cohorts. Am J Respir Crit Care Med. 2017 Feb 15;195(4):473-481. doi: 10.1164/rccm.201607-1330OC. PMID: 27579823.
- Gomez JC, Dang H, Martin JR, Doerschuk CM. Nrf2 modulates host defense during Streptococcus pneumoniae pneumonia in mice. J Immunol. 2016 Oct 1;197(7):2864-79. doi: 10.4049/jimmunol.1600043. Epub 2016 Aug 26. PMID: 27566827; PMCID: PMC5026972.
- Sun W, Kechris K, Jacobson S, Drummond MB, Hawkins GA, Yang J, Chen TH, Quibrera PM, Anderson W, Barr RG, Basta PV, Bleecker ER, Beaty T, Casaburi R, Castaldi P, Cho MH, Comellas A, Crapo JD, Criner G, Demeo D, Christenson SA, Couper DJ, Curtis JL, Doerschuk CM, Freeman CM, Gouskova NA, Han MK, Hanania NA, Hansel NN, Hersh CP, Hoffman EA, Kaner RJ, Kanner RE, Kleerup EC, Lutz S, Martinez FJ, Meyers DA, Peters SP, Regan EA, Rennard SI, Scholand MB, Silverman EK, Woodruff PG, O’Neal WK, Bowler RP; SPIROMICS Research Group; COPDGene Investigators. Common genetic polymorphisms influence blood biomarker measurements in COPD. PLoS Genet. 2016 Aug 17;12(8):e1006011. doi: 10.1371/journal.pgen.1006011. eCollection 2016 Aug PMID: 27532455; PMCID: PMC4988780.
- Hua X, Naselsky WC, Jania CM, Chason KD, Huang JJ, Doerschuk CM, Graham SM, Senior BA, Tilley SL. Mast cell deficiency limits the development of chronic rhinosinusitis in mice. Ann Otol Rhinol Laryngol. 2016 Apr;125(4):290-6. doi: 10.1177/0003489415610775. Epub 2015 Dec 17. PMID: 26681624.
- 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. 2016 Feb;54(2):210-21. doi: 10.1165/rcmb.2014-0111OC. Epub 2015 Jun 29. PubMed PMID: 26121027; PubMed Central PMCID: PMC4821038.
- 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.
- 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.
- 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.
- 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.