G. Scott Worthen, MD

Locations: Main Campus
Appointments and Referrals: 1-800-TRY-CHOP (1-800-879-2467)

  • Background

    Our laboratory is interested in the mechanisms by which polymorphonuclear leukocytes (neutrophils) are attracted to, and potentially injure, the lung. The lung has a unique architecture and physiology that results in a large number of neutrophils within the lung microcirculation under even normal circumstances. Following an inflammatory response in the lung, neutrophils are further recruited from the bone marrow into the circulation, and thence are avidly retained within the lung. We are interested in mechanisms of recruitment during inflammation, as well as the feedback loops that control neutrophil number under both homeostatic and inflammatory conditions.

    Neutrophil number in the circulation is regulated in a complex fashion that senses neutrophil accumulation at a sentinel site, which we believe is the gut. Chemokine CXCL5 secretion by the gut epithelium attracts neutrophils, which are then sensed by phagocytic cells that secrete a variety of cytokines. Recognition of neutrophils is accompanied by decreased secretion of IL-l and IL-23, cytokines which drive differentiation of IL-17-producing cells. IL-17 in tum, then induces production of G-CSF and other CXC chemokines, thus contributing to release of neutrophils from the bone marrow. Somewhat surprisingly, the gut microbiome is involved in establishing the "setpoint" for these cytokines, and hence the neutrophil number. This complex feedback system is deranged in mice deficient in CXCL5, or the receptor for CXC chemokines, CXCR2. It is also abnonnal in mice and humans deficient in CD18.

    Within Neonatology, we are particularly interested in the period during which the neonate acquires its repertoire of microbes in the gut and other sites. We are interested in the idea that this process sets in motion this feedback mechanism, and thus may be critically important for the adaptation of neonates to a world containing microbes.

  • Education and Training

    Medical School

    MD - Harvard Medical School, Boston, MA

    Internship

    Beth Israel Hospital, Boston, MA

    Residency

    Beth Israel Hospital, Boston, MA

    Fellowship

    Pulmonary Medicine - University of Colorado School of Medicine, Denver, CO

    Board Certification

    Internal medicine
    Pulmonary Medicine
    Critical Care Medicine

  • Titles and Academic Titles

    Physician-Scientist in Neonatology

    Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania

  • Centers and Programs
  • Publications

    Papers

    2012

    Floros J, Londono D, Gordon D, Silveyra P, Diangelo SL, Viscardi RM, Worthen GS, Shenberger J, Wang G, Lin Z, Thomas NJ. IL-18R1 and IL-18RAP SNPs may be associated with bronchopulmonary dysplasia in African-American infants. Pediatr Res. 71(1):107-114, Jan 2012. PMC3610412

    Mei J, Liu Y, Dai N, Hoffmann C, Hudock KM, Zhang P, Guttentag SH, Kolls JK, Oliver PM, Buslunan FD, Worthen GS. Cxcr2 and Cxcl5 regulate the IL-17/G-CSFaxis and neutrophil homeostasis in mice. J. Clin Invest. 122(3):974-986, Mar 2012. PMC3287232

    Ramon H.E., Beal A., Liu Y, Worthen G.S., and P. M. Oliver. The E3 ubiquitin ligase adaptor Ndfip 1 regulates Th17 differentiation by limiting the production of proinflammatory cytokines. J ImmunoI. 188(8):4023-4031, Apr 2012. PMC3713491

    Balamayooran G, Batra S, Cai S, Mei J, Worthen GS, Penn AL, Jeyaseelan S. Role of CXCL5 in leukocyte recruitment to the lungs during secondhand smoke exposure. 2012 Am J Resp Cell Mol BioI. 47(1):104-111, Ju12012. PMC3402800

    Fridlender ZG, Sun J, Mishalian I, Singhal S, Cheng G, Kapoor V, Homg W, Fridlender Bayuh R, Worthen GS, Albelda SM. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One. http://www.ncbi.nlm.nih.gov/pubmedI22348096 7(2):e31524, 2012. PMC3279406

    Hudock KM, Liu Y, Mei J, Marino RC, Hale JE, Dai N, Worthen GS. Delayed resolution of lung inflammation in Il-1rn-/- mice reflects elevated IL-17/G-CSF expression. Am J Respir Cell Mol BioI. 47:436-444, Oct 2012. PMC3488622 

    2011

    Liu Y, Mei J. Gonzales L, Yang G, Dai N, Wang P, et al. IL-17A and TNF-α exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J Immunol. 2011 Mar 1;186(5):3197-205. Epub Jan 31. Cited in PubMed; PMID 21282514. Read the abstract

    2010

    Fuentes R, Wang Y, Hirsch J, Wang C, Rauova L, Worthen GS. Infusion of mature megakaryocytes into mice yields functional platelets. J Clin Invest. 2010 Nov 1;120(11):3917-22. doi: 10.1172/JC143326. Epub 2010 Oct 25. Cited in PubMed; PMID 20972336. Read the article

    Mei J, Liu Y, Dai N, Favara M, Greene T, Jeyaseelan S, et al. CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection. Immunity. 2010 Jul 23;3(1):106-17. Cited in PubMed; PMID 20643340. Read the abstract

    2009

    Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009 Sep 8;16(3):183-94. Cited in PubMed; PMID 19732719. Read the article 

    Cai S, Zemans RL, Young SK, Worthen GS, Jeyaseelan S. Myeloid differentiation protein-2-dependent and -independent neutrophil accumulation during Escherichia coli pneumonia. Am J Respir Cell Mol Biol. 2009 Jun;40(6):701-9. Epub 2008 Nov 6. Read the article

    Zemans RL, Briones N, Young SK, Malcolm KC, Refaeli Y, Downey GP, et al. A novel method for long term bone marrow culture and genetic modification of murine neutrophils via retroviral transduction. J Immunol Methods. 1009 Jan 30;340(2):102-15. Epub 2008 Nov 14. Cited in PubMed; PMID 19010330. Read the article

     

     

  • Editorial and Academic Positions

    Academic and institutional committees

    2009-present, IACUC, The Children's Hospital of Philadelphia
    2013-present, Executive committee Center for Lung Biology, University of Pennsylvania