Research Focus

Inflammation is a vital process of tissue repair following lung injury. Through their ability to clear neutrophils and release anti-inflammatory cytokines, macrophages are important effector cells mediating the resolution of inflammation. The matrix metalloproteinases (MMPs), which are balanced by their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), control both pro- and anti-inflammatory processes.

My laboratory is focused on TIMP3, which is expressed by macrophages in vitro and can inhibit many MMPs and members of the ADAM/ADAMTS family (a disintegrin and metalloproteinase). Thus, we have been examining the role of TIMP3 in acute lung injury using the well-established bleomycin-toxicity model. We have demonstrated that mice lacking TIMP3 (Timp3-/-)have markedly increased neutrophil influx that persists well after the resolution of inflammation in wild type (WT) mice. Although we have found no difference in the levels of neutrophil chemokines, especially those primarily produced by resident cells, neutrophil chemotaxis to bronchoalveolar lavage (BAL) fluid from Timp3-/- mice was significantly increased. Furthermore, we have recently determined that compared to cells from WT mice, macrophages from Timp3-/- mice express higher levels of M1 (pro-inflammatory) and lower levels of M2 (anti-inflammatory) activation markers. Based on these findings, we hypothesize that TIMP3 facilitates the resolution of inflammation by controlling macrophage polarization–specifically by moderating the activation of M1 cells and promoting the differentiation of M2 macrophages (Fig. 1). We are currently testing these ideas and our ongoing work is focused on identifying the mechanism through which TIMP3 regulates macrophage polarization and determining specifically how TIMP3 moderates neutrophil chemotaxis following acute lung injury.

We have also begun to expand our acute lung injury studies to include proteins known to interact with TIMP3. TIMP3 is thought to be the physiological inhibitor of ADAM17 (also known as TNFα Converting Enzyme or TACE). Furthermore, localization of TIMP3 to appropriate compartments is regulated, at least in part, through interaction with sulfated glycosaminoglycans. Thus, our continued studies include examining the role of ADAM17 from either leukocytes or lung epithelial cells in regulation of the inflammatory response following acute lung injury. We have also begun studies to determine the role of endogenous sulfated glycosaminoglycans in controlling leukocyte activation following lung injury or infection.
Together, these studies will allow us to identify factors involved in the resolution of inflammation and fibrosis. Working with the Timp3-/- mice, as well as mice lacking ADAM17 in leukocytes or epithelial cells will provide us with models to dissect the key pathways and their role in other relevant experimental models, such as infection.

Relevant Publications

Gill S.E., Wight T.N., and Frevert C.W. (2010) Proteoglycans: Key Regulators of Pulmonary Inflammation and the Innate Immune Response to Lung Infection. Anat Rec (Hoboken). 293(6): 968-81.

Hu J.H., Du L., Chu T., Otsuka G., Dronadula N., Jaffe M., Gill S.E., Parks W.C., and Dichek D.A. (2010) Overexpression of urokinase by plaque macrophages causes histologic features of plaque rupture and increases vascular MMP activity in older apoE-null mice. Circulation. 121(14): 1637-44.

Tanino Y., Coombe D.R., Gill S.E., Kett W.C., Kajikawa O., Proudfoot A.E.I., Wells T.N.C., Wight T.N., Martin T.R., and Frevert C.W. (2010) Kinetics of Chemokine-Glycosaminoglycan Interactions Control Neutrophil Migration into the Airspaces of the Lungs. J Immunol. 184(5): 2677-85.

Gill S.E., Huizar I., Bench E.M., Sussman S.W., Wang Y., Khokha R., and Parks W.C. (2010) Tissue inhibitor of metalloproteinases 3 regulates resolution of inflammation following acute lung injury. Am J Pathol.176 (1): 64-73.

Gill S.E., Kassim S.Y., Birkland T.P., and Parks W.C. (2010) Mouse Models of MMP and TIMP Function. Methods Mol Biol (Ed: Clark IM). 622:31-52.

Gill S.E. and Parks W.C. (2008) Metalloproteinases and their inhibitors: Regulators of wound healing. Int J Biochem Cell B. 40: 1334-1347.

Gill S.E., Pape M.C., and Leco K.J. (2006) Regulation of extracellular matrix-cell signaling by tissue inhibitor of metalloproteinases-3 (TIMP-3) during murine bronchiole branching morphogenesis.  Dev Biol. 298:  540-554.

Active Funding