Research Interests:
The primary focus of the laboratory is to understand the molecular and cellular mechanisms involved in the immunotoxic responses to various particles, including silica, asbestos and nanoparticles, which lead to lung injury. We have recently identified the activation of lung mast cells as a critical step in the initiation and progression of pulmonary inflammation and fibrosis following particle exposure.
Mast cells have long been recognized for their role in the genesis of allergic inflammation and more recently for their participation in innate and acquired immune responses. Mast cells reside within tissues including the skin and respiratory tract where they interface with the external environment. This allows for their interaction with not only allergens, bacteria and viruses, but also with any potential toxic chemicals, metals or particles. Further, mast cells have been found to participate in wound healing, cardiovascular disease, fibrosis and autoimmunity in addition to allergic disease.
Current and future studies are aimed at: (I) further delineating the role of mast cells and mast cell derived products in lung injury following exposure to immunotoxic particles; (II) elucidating the role of various receptors, including scavenger receptors, which are involved in the recognition of particles by mast cells and the subsequent signaling pathways leading to mast cell activation; (III) begin to identify new strategies for the treatment of environmentally mediated diseases through the therapeutic targeting of mast cells.
Mast Cell Interaction with Silica Particles
Selected Publications:
Knisz J, Banks A, McKeag L, Metcalfe DD, Rothman PB, Brown JM. Loss of SOCS7 in Mice Results in Severe Cutaneous Disease and Increased Mast Cell Activation. Clinical Immunology, 2009.
Németh K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Xuzhen H, Jelinek I, Star RA, Mezey E. Bone Marrow Stromal Cells Attenuate Sepsis via Prostaglandin E2-dependent Reprogramming of Host Macrophages to Increase their Interleukin-10 Production. Nature Medicine, 2008; 15(1): 42-49.
Brown JM, Wilson TM, Metcalfe DD. The Mast Cell and Allergic Diseases: Role in Pathogenesis and Implications for Therapy. Clinical and Experimental Allergy, 2008; 38(1):4-18.
Pfau JC, Sentissi JJ, Blake DJ, Li S, Calderon-Garciduenas L, Brown JM. Asbestos Induced Autoimmunity in C57Bl/6 Mice. Journal of Immunotoxicology, 2008; 5(2):129-137.
Brown JM*, Soule BP*, Kushnir-Sukhov NM, Simone NL, Mitchell JB, Metcalfe DD. Effects of Gamma Radiation on FcεRI and Toll-Like Receptor Mediated Mast Cell Activation. Journal of Immunology, 2007; 179(6):3277-3286. *Co-First Authorship
Brown JM, Swindle EJ, Kushnir-Sukhov NM, Holian A, Metcalfe DD. Silica Directed Mast Cell Activation is Enhanced by Scavenger Receptors. American Journal of Respiratory Cell and Molecular Biology, 2007; 36:43-52.
Kushnir-Sukhov NM, Gilfillan AM, Coleman JW, Brown JM, Bruening S, Toth M, Metcalfe DD. 5-Hydroxytryptamine Induces Mast Cell Adhesion and Migration. Journal of Immunology, 2006; 177:6422-6432.
Brown JM, Schwanke CM, Pershouse MA, Pfau JC, Holian A. Effects of Rottlerin on Silica-Exacerbated Systemic Autoimmune Disease in New Zealand Mixed Mice. American Journal of Physiology: Lung Cellular and Molecular Physiology, 2005; 289:990-998.
Brown JM, Pfau JC, Pershouse MA, Holian A. Silica, Apoptosis, and Autoimmunity. Journal of Immunotoxicology, 2004; 1(3-4):177-188.
Pfau JC, Brown JM, Holian A. Silica-Exposed Mice Generate Autoantibodies to Apoptotic Cells. Toxicology, 2004; 195/2-3:167-176.
Brown JM, Pfau JC, Holian A. Immunoglobulin and Lymphocyte Responses Following Silica Exposure in New Zealand Mixed Mice. Inhalation Toxicology, 2004; 16:133-139.
Hassani M, Brown JM, Morandi MT, Holian A. Particulate Matter Immunomodulatory Effects on Autoantibody Production in New Zealand Mixed Mice. Journal of Immunotoxicology, 2004; 1(2):95-102.
Brown JM, Archer AJ, Pfau JC, Holian A. Silica Accelerated Systemic Autoimmune Disease in Lupus Prone New Zealand Mixed Mice. Clinical and Experimental Immunology, 2003; 131:415-421.
