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

Smith TJ, Tsai CC, Shih MJ, Tsui S, Chen B, Han R, Naik V, King CS, Press C, Kamat S, Goldberg RA, Phipps RP, Douglas RS, Gianoukakis AG. Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy. Thyroid. 2008 Sep;18(9):983-988.

Lehmann GM, Feldon SE, Smith TJ, Phipps RP. Immune mechanisms in thyroid eye disease. Thyroid. 2008 Sep;18(9):959-965.

Bernard MP, Bancos S, Sime PJ, Phipps RP. Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise. Curr Pharm Des. 2008;14(21):2051-2060.

Thatcher TH, Benson RP, Phipps RP, Sime PJ. High Dose but not Low Dose Mainstream Cigarette Smoke Suppresses Allergic Airway Inflammation by Inhibiting T Cell Function. Am J Physiol Lung Cell Mol Physiol. 2008 Jun 20.

Garcia-Bates TM, Lehmann GM, Simpson-Haidaris PJ, Bernstein SH, Sime PJ, Phipps RP Role of peroxisome proliferator-activated receptor gamma and its ligands in the treatment of hematological malignancies. PPAR Res. 2008;2008:834612. PMID: 18528522.

Lehmann GM, Garcia-Bates TM, Smith TJ, Feldon SE, Phipps RP. Regulation of Lymphocyte Function by PPARgamma: Relevance to Thyroid Eye Disease-Related Inflammation. PPAR Res. 2008;2008:895901. PMID: 18354731.

Spinelli SL, O’Brien JJ, Bancos S, Lehmann GM, Springer DL, Blumberg N, Francis CW, Taubman MB, Phipps RP. The PPAR-Platelet Connection: Modulators of Inflammation and Potential Cardiovascular Effects. PPAR Res. 2008;2008:328172. PMID: 18288284.

Edirisinghe I, Yang SR, Yao H, Rajendrasozhan S, Caito S, Adenuga D, Wong C, Rahman A, Phipps RP, Jin ZG, Rahman I. VEGFR-2 inhibition augments cigarette smoke-induced oxidative stress and inflammatory responses leading to endothelial dysfunction. FASEB J. 2008 Jul;22(7):2297-2310. Epub 2008 Feb 8. PMID: 18263699

Ray DM, Spinelli SL, Pollock SJ, Murant TI, O’Brien JJ, Blumberg N, Francis CW, Taubman MB, Phipps RP. Peroxisome proliferator-activated receptor gamma and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles. Thromb Haemost. 2008 Jan;99(1):86-95.

Cholette JM, Blumberg N, Phipps RP, McDermott MP, Gettings KF, Lerner NB. Developmental changes in soluble CD40 ligand. J Pediatr. 2008 Jan;152(1):50-54, 54.e1.

Caito S, Yang SR, Kode A, Edirisinghe I, Rajendrasozhan S, Phipps RP, Rahman I. Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages. Antioxid Redox Signal. 2008 Feb;10(2):253-260.

Bernard MP, Phipps RP. CpG oligodeoxynucleotides induce c1yclooxygenase-2 in human B lymphocytes: implications for adjuvant activity and antibody production. Clin Immunol. 2007 Nov;125(2):138-148.

Lakatos HF, Thatcher TH, Kottmann RM, Garcia TM, Phipps RP, Sime PJ. The Role of PPARs in Lung Fibrosis. PPAR Res. 2007;2007:71323.

Ryan EP, Bushnell TP, Friedman AE, Rahman I, Phipps RP. Cyclooxygenase-2 independent effects of cyclooxygenase-2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B-cells. Cancer Immunol Immunother. 2008 Mar;57(3):347-358.