Nancy E. Dunlap, M.D. Endowed Chair in Pulmonary Disease
Department of Medicine
Division of Pulmonary, Allergy and Critical Care
|Address:||McCallum Bldg, room 896
Birmingham, AL 35294
B.S., University of Florida, 1971
Ph.D., University of Florida, 1976
Post-doctoral Fellow, University of Texas Medical Branch, Galveston, TX
Unrelenting neutrophilic inflammation is a driving force in many human diseases. Research in the Blalock laboratory has focused on understanding the cause(s) of and potential treatments for this aberrant process. In what some consider a paradigm altering observation, the group has found that at inflammatory sites, neutrophil degradation of connective tissue proteins generates novel peptide fragments that can attract a new wave of neutrophils. In certain individuals, it is believed that this neutrophil-mediated process becomes uncontrolled, leading to self-propagating inflammation and chronic disease. In particular, a tripeptide (proline-glycine-proline, PGP) derived from collagen fragmentation, has been shown to attract and activate neutrophils via receptors previously thought to be only utilized by classical chemokines such as interleukin-8 (IL-8).
Moreover, chronic administration of this peptide into the airways of experimental animals causes robust neutrophil influx and a disease similar to emphysema with alveolar enlargement and right ventricular hypertrophy. Consequently, the research has focused on airway disorders characterized by a chronic neutrophilic inflammation such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and lung transplantation organ rejection. In COPD and CF, these researchers have apparently identified a unique proteolytic pathway leading to collagen breakdown and PGP generation. This seems to involve matrix metalloproteases (MMPs) and a novel serine protease, prolyl endopeptidase (PE); these enzymes have been found to be elevated in these disorders. Collectively, these findings have far-reaching translational potential for human pulmonary disorders, in particular, and chronic inflammatory diseases, in general. This is rapidly being implemented in the diagnostic arena where PGP and certain isoforms appear to be biomarkers for COPD, CF, and chronic lung transplant rejection. Future studies will examine whether PGP and its isoforms are prognostic for disease progression and efficacy of certain therapeutic regimens. Rational drug design has led to the development of a variety of PGP antagonists and MMP/PE inhibitors that target this novel pathway of neutrophilic inflammation and, consequently, are prototypes for drugs to treat chronic inflammatory conditions.