Paul Wolters, MD
Research Interests
One area of investigation in my lab is directed toward understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis is believed to be the sequela of abnormal healing of the lung in response to an injury and is characterized by lung injury, destruction of normal lung architecture, and abnormal deposition of collagens. A prominent feature of this disease is the organization of fibroblasts in specific regions of the lung termed fibroblast foci. Why the IPF fibroblasts organize into specific foci and why they secrete excessive quantities of collagen that cause fibrosis is unknown. One hypothesis is that the fibroblasts are intrinsically abnormal and that there abnormal phenotype drives the fibrotic process. To investigate this hypothesis, we have been using gene-profiling techniques to phenotype fibroblasts obtained from IPF patients with the objective of identifying and characterizing genes uniquely expressed in these cells that contribute to the fibrotic process.
The second area of investigation is directed toward understanding the role mast cells play in regulating the host response to bacterial lung infections. Mast cells are innate immune cells that are widely distributed in most tissues. Within lung, they reside adjacent to airway epithelium, placing them in an ideal location to act as early sensors of bacterial infection. This role is supported by reports that mast cell derived TNF-a is required for host survival following bacterial lung infections. Our recent work, complements these reports by showing that the mast cell protease dipeptidyl peptidase I (DPPI) contributes to death of the host from septic peritonitis and bacterial lung infections. Thus, mast cell proteases and cytokines coordinate defense against bacterial lung infections. While coordinating this defense, some mast cell mediators protect the host and improve survival while others harm the host and worsen survival. Future directions in the lab will be aimed at identifying how mast cells recognize the presence of bacterial infections, what mediators they release when activated by bacteria, and how these mediators influence host survival during the response to infection.
Selected Publications
Sun J*, Sukhova GK*, Wolters PJ*, Yang M, Kitamoto S, Libby P, MacFarlane LA, Mallen-St. Clair J, and Shi GP. Mast Cells Promote Atherosclerosis by Releasing Pro-Inflammatory Cytokines. (*contributed equally) (In press at Nature Medicine).
Xu X, Zhang D, Wolters PJ, Killeen NP, Sullivan BM, Locksley RM, and Caughey GH. Neutrophil Histamine Contributes to Inflammation in Mycoplasma Pneumonia. J Exp Med. 2006; 203: 2907-2917.
Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, and Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 2006; 103: 13180-13185.
Mallen-St. Clair J, Shi GP, Chapman HA, and Wolters PJ. Cathepsins L and S are not Required for Activation of Dipeptidyl Peptidase I (Cathepsin C) in Mice. Biological Chemistry. 2006; 387:1143-6
Wolters PJ, Mallen-St. Clair J, Lewis CC, Villalta SA, Baluk P, Erle DJ, and Caughey GH. Tissue-Selective Mast Cell Reconstitution and Differential Lung Gene Expression in Mast Cell-Deficient KitW-sh/KitW-sh Sash Mice. Clin Exp Allergy 2005; 35:82-8.
Mallen-St. Clair J, Pham CTN, Villalta SA, Caughey GH, and Wolters PJ. Mast Cell Dipeptidyl Peptidase I Mediates Survival From Sepsis. J Clin Invest 2004; 113: 628-635.
Henningsson F, Wolters PJ, Chapman HA, Caughey GH, and Pejler G. Mast Cell Cathepsins C and S Control Levels of Carboxypeptidase A and the Chymase, Mouse Mast Cell Protease 5. Biol Chem 2003; 384:1527-31.
Wolters PJ, Pham CTN, Muillenberg D, Ley TJ, and Caughey GH. Dipeptidyl Peptidase I is Essential for the Activation of Mast Cell Chymase, But Not Tryptase in vivo. J Biol Chem 2001; 276: 18551-18556.
Wolters PJ, and Chapman HA. Importance of Lysosomal Cysteine Proteases in Lung Disease. Respiratory Research 2000; 1: 170-177.
Caughey, GH, Raymond WW, and Wolters, PJ. Angiotensin II Generation by Mast Cell a- and b- Chymases. Biochem Biophys Res Commun 2000; 1480: 245-257.
Wolters PJ, Laig-Webster M, and Caughey GH. Dipeptidyl Peptidase I Cleaves Matrix-Associated Proteins and is Expressed Mainly by Mast Cells in Normal Dog Airways. Am J Respir Cell Mol Biol 2000; 22: 183-190.
Wolters PJ, Raymond WW, Blount JL, Caughey GH. Regulated expression, Processing, and Secretion of Dog Mast Cell Dipeptidyl Peptidase I. J Biol Chem 1998; 273: 15514-15520.s