Cellular and molecular characterization of fibroblasts as mediators of inflammation, wound healing and fibrosis: Injury to the lung from exposure to chemotherapeutic agents, irradiation, or occupational hazards such as pesticides, may lead to pulmonary fibrosis. The advanced stages of this disease are characterized by a fibroblast hyperplasia and by excessive accumulation of fibroblast-secreted connective tissue such as collagen.

       This laboratory is investigating whether subpopulations of fibroblasts exist and if so, their role in lung inflammation and fibrosis. We were the first to prove that lung fibroblasts are divisible into two major populations based on expression of the Thy-1 antigen. Our observations indicate that Thy 1+ fibroblasts mediate the bulk of tissue repair while the Thy-1- subset regulates inflammation, which typically precedes fibrosis. Our studies support the hypothesis that the fibroblast is not simply a target for cytokines produced by cells such as macrophages and T lymphocytes, but that differential production of cytokines by fibroblast subsets regulate the activities of cells of the immune system which inhabit the lung.

      Current efforts are directed at determining how a surface receptor called CD40 regulates fibroblast proliferation, cytokine production, interaction with lymphocytes and proliferation. Understanding the activities of fibroblasts will permit the design of more rational approaches to arrest or reverse potentially fatal and untreatable pulmonary fibrotic disease.

Technology Transfer and Business Development Successes:

• Successfully evaluated a new chemokine receptor antagonist to help prevent cigarette smoke lung damage using a preclinical animal model. Efficacy in the preclinical model supported moving forward with a clinical trial.
• Prior success with Biogen, Schering-Plough providing technical expertise, preclinical models of lung scarring and primary human cells for drug evaluation.
• Prior success with Boeringer Ingelheim, Bausch & Lomb, and American Home Products. These efforts involved providing scientific expertise, in vitro testing of lead compounds, and tests for efficacy in animal models of scarring and inflammation. New findings permitted lead compounds to move forward toward clinical testing.

Recent Publications

Thatcher TH, Maggirwar SB, Baglole CJ, Lakatos HF, Gasiewicz TA, Phipps RP, Sime PJ. 2007 . Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB. Am J Pathol. Mar;170(3):855-864.

Ruckerl R, Phipps RP, Schneider A, Frampton M, Cyrys J, Oberdorster G, Wichmann HE, Peters A. 2007. Ultrafine particles and platelet activation in patients with coronary heart disease - results from a prospective panel study. Part Fibre Toxicol. Jan 22;4:1.

O’Brien JJ, Ray DM, Spinelli SL, Blumberg N, Taubman MB, Francis CW, Wittlin SD, Phipps RP. 2007. The platelet as a therapeutic target for treating vascular diseases and the role of eicosanoid and synthetic PPARgamma ligands. Prostaglandins Other Lipid Mediat. Jan;82(1-4):68-76. Epub 2006 Jul 10. Review.

Ryan EP, Pollock SJ, Kaur K, Felgar RE, Bernstein SH, Chiorrazi N, Phipps RP. 2006. Constitutive and activation-inducible cyclooxygenase-2 expression enhances survival of chronic lymphocytic leukemia B cells. Clin Immunol. Jul;120(1):76-90

Baglole CJ, Bushinsky SM, Garcia TM, Kode A, Rahman I, Sime PJ, Phipps RP. 2006. Differential induction of apoptosis by cigarette smoke extract in primary human lung fibroblast strains: implications for emphysema. Am J Physiol Lung Cell Mol Physiol. Jul;291(1):L19-29.

Phipps, R.P., Beckett, W., Kaufman, J., Martey, C., Sime, P. J., and Thatcher, T. 2005. Anti-inflammatory therapies for lung injury. In: Lung injury: Mechanisms, pathophysiology and therapy. Notter, R., Finkelstein, J. and Holm, B. Eds., Taylor & Francis, Pp 573-616.

Baglole, C.J., Smith, T.J., Foster, D., Sime, P.J., Feldon, S., and Phipps, R.P. 2005. Functional assessment of fibroblast heterogeneity by the cell-surface glycoprotein Thy-1. In: Myofibroblasts, Editor: G. Gabbiani, C. Chaponnier, A. Desmouliere.

Feldon SE, Park DJ, O'Loughlin CW, Nguyen VT, Landskroner-Eiger S, Chang D, Thatcher TH, Phipps RP. 2005. Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves' ophthalmopathy. Invest Ophthalmol Vis Sci. Nov;46(11):3913-3921.

Purkerson JM, Smith RS, Pollock SJ, Phipps RP. 2005. The TRAF6, but not the TRAF2/3, binding domain of CD40 is required for cytokine production in human lung fibroblasts. Eur J Immunol. Oct;35(10):2920-2928.

Baglole CJ, Reddy SY, Pollock SJ, Feldon SE, Sime PJ, Smith TJ, Phipps RP. 2005. Isolation and phenotypic characterization of lung fibroblasts. Methods Mol Med. 117:115-127.

Martey CA, Baglole CJ, Gasiewicz TA, Sime PJ, Phipps RP. 2005. The aryl hydrocarbon receptor is a regulator of cigarette smoke induction of the cyclooxygenase and prostaglandin pathways in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol. Sep;289(3):L391-399.

Thatcher TH, McHugh NA, Egan RW, Chapman RW, Hey JA, Turner CK, Redonnet MR, Seweryniak KE, Sime PJ, Phipps RP. 2005. Role of CXCR2 in cigarette smoke-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol. Aug;289(2):L322-328.

Ray DM, Akbiyik F, Bernstein SH, Phipps RP. 2005. CD40 engagement prevents peroxisome proliferator-activated receptor gamma agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-kappaB-dependent mechanism. J Immunol. Apr 1;174(7):4060-4069.

Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, Phipps RP, Sime PJ. 2005. PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol. Jun;288(6):L1146-1153.

Ryan EP, Pollock SJ, Murant TI, Bernstein SH, Felgar RE, Phipps RP. 2005. Activated human B lymphocytes express cyclooxygenase-2 and cyclooxygenase inhibitors attenuate antibody production. J Immunol. Mar 1;174(5):2619-2626. Erratum in: J Immunol. 2005 Apr;174(8):5134. Pollack, Stephen J [corrected to Pollock, Stephen J].

O’Reilly KM, Phipps RP, Thatcher TH, Graf BA, Van Kirk J, Sime PJ. 2005. Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. Jun;288(6)