Jacob N. Finkelstein Professor of Pediatrics, Environmental Medicine, and Radiation Oncology B.S. 1971 (Carnegie Mellon) Ph.D. 1976 (Northwestern University) E-Mail: Jacob_Finkelstein@urmc.rochester.edu

My laboratory is actively involved in investigating the development and maintenance of differentiated functions of the pulmonary alveolar epithelium and the role of specific cell-cell interactions in controlling developmental processes. Within this broad framework, our laboratory is proceeding with a number of specific projects to more clearly define the cellular and molecular control mechanisms which are critical to lung development and repair in response to tissue and cell injury. To address this broad question the laboratory has developed a number of in vivo and in vitro models to permit detailed and specific analysis of cell specific gene expression.

A major aspect of the work in the laboratory is focused on the control of lung parenchymal cell proliferation during development and especially during tissue repair after injury. The type II cell plays an important role as the stem cell for renewal of the alveolar epithelium both in the normal lung and especially during lung injury resulting in type I cell epithelial death.

Our current working hypothesis is that many of these processes are regulated through intercellular communication by the production of and response to specific mediators or "growth factors" whose role it is to modulate and program cellular functions. The overall goal of this work is to identify the specific mediators produced by the type II cell following injury and to identify the key control mechanisms which are involved in these responses. Such information would be valuable in determining how lung growth and repair of epithelial damage are regulated during normal and pathological circumstances. The regeneration of the alveolar epithelium after severe tissue injury, induced by systemic or inhaled agents, requires the induction of controlled proliferation and differentiation of the alveolar type II cell. We have identified a number of key regulatory growth factors which induce epithelial proliferation and differentiation, and are actively synthesized and secreted by inflammatory cells. We are currently purifying these factors and cloning the specific genes. We are also characterizing the receptors for these substances on the epithelial cell surface and plan to examine their role during normal lung growth.

Proliferation of pulmonary fibroblasts and enhanced production of extracellular matrix components by these cells results in tissue fibrosis and subsequent degradation of lung function. Factors which may control the responses of fibroblasts in the lung are not clearly defined. Inflammatory cells are known to produce various cytokines/growth factors which can modulate some aspects of fibroblast growth. The potential interactions between the alveolar epithelium and interstitial fibroblasts have not been investigated. We suggest that the type II cell may act to control fibroblast function through the production of specific growth factors. Further, the production of these factors is altered by type II cell injury.

A third area of investigation addresses the role of epithelial derived factors in the regulation of inflammatory cell recruitment and activation. Although inflammation is a well known consequence of inhaled toxicants, the source of the obligate chemotactic or activating signals is poorly understood. Furthermore, the regulation and source of production of anti-inflammatory cytokines remain to be elucidated. Using well-characterized models of inflammation, we have identified changes in proinflammatory gene abundance in epithelial cells and are examining the transcriptional and post-transcriptional regulation of these genes in pulmonary epithelial and resident inflammatory cells.

Taken together, these data suggest the existence of a complex intercellular communication network that plays a key role in determining overall tissue response to exogenous stresses.

Pryhuber GS, Huyck HL, Bhagwat S, O’Reilly MA, Finkelstein JN, Gigliotti F, Wright TW. Parenchymal Cell TNF Receptors Contribute to Inflammatory Cell Recruitment and Respiratory Failure in Pneumocystis carinii-Induced Pneumonia. J Immunol. 2008 Jul 15;181(2):1409-1419.

Bruckner L, Gigliotti F, Wright T, Harmsen A, Notter RH, Chess P, Wang Z, Finkelstein J. 2006. Pneumocystis carinii infection sensitizes lung to radiation-induced injury after syngeneic marrow transplantation: role of CD4+ T cells. Am J Physiol Lung Cell Mol Physiol. Jun;290(6):L1087-1096.

Vitiello PF, Staversky RJ, Gehen SC, Johnston CJ, Finkelstein JN, Wright TW, O’Reilly MA. 2006. p21Cip1 protection against hyperoxia requires Bcl-XL and is uncoupled from its ability to suppress growth. Am J Pathol. Jun;168(6):1838-1847.

Elder A, Gelein R, Finkelstein JN, Driscoll KE, Harkema J, Oberdorster G. 2005. Effects of Subchronically Inhaled Carbon Black in Three Species. I. Retention Kinetics, Lung Inflammation, and Histopathology. Toxicol Sci. Sep 21; [Epub ahead of print]

Elder A, Johnston C, Gelein R, Finkelstein J, Wang Z, Notter R, Oberdorster G. 2005. Lung inflammation induced by endotoxin is enhanced in rats depleted of alveolar macrophages with aerosolized clodronate. Exp Lung Res. Jul-Aug;31(6):527-546.

Elder AC, Gelein R, Oberdörster G, Finkelstein J, Notter R, and Wang Z. 2005. Efficient depletion of alveolar macrophages using intratracheally inhaled aerosols of liposome-encapsulated clodronate. Exp Lung Res. Mar;30(2):105-120.

Johnston CJ, Holm BA, Finkelstein JN. 2005. Sequential exposures to ozone and lipopolysaccharide in postnatal lung enhance or inhibit cytokine responses. Exp Lung Res. May;31(4):431-447.

Singal M, Finkelstein JN. 2005. Use of indicator cell lines for determining inflammatory gene changes and screening the inflammatory potential of particulate and non-particulate stimuli. Inhal Toxicol. Aug;17(9):415-425

Singal M, Finkelstein JN. 2005. Amorphous silica particles promote inflammatory gene expression through the redox sensitive transcription factor, AP-1, in alveolar epithelial cells. Exp Lung Res. Jul-Aug;31(6):581-597.

Chess PR, O’Reilly MA, Sachs F, Finkelstein JN. 2005. Reactive oxidant and p42/44 MAP kinase signaling is necessary for mechanical strain-induced proliferation in pulmonary epithelial cells. J Appl Physiol. Sep;99(3):1226-1232.

Wang J, Gigliotti F, Maggirwar S, Johnston C, Finkelstein JN, Wright TW. 2005. Pneumocystis carinii activates the NF-kappaB signaling pathway in alveolar epithelial cells. Infect Immun. May;73(5):2766-2777.