Lung injury results in patterns of cytokine and peptide growth factor production which are temporally and spatially specific. These factors act in an autocrine and paracrine fashion to regulate the remodeling of peripheral airways, alveoli, and capillaries during lung repair. Time and position restricted expression of these factors also occurs during normal lung morphogenesis. Thus morphogenesis serves as a paradigm for lung repair, and Vice Versa. Hepatocyte Growth Factor/Scatter Factor (HGF/SF) is a cytokine which is itself regulated by proinflammatory cytokines present during lung injury and inflammation, and has important effects on morphogenesis and tissue repair. We hypothesize that the inability to express functional HGF/SF protein will adversely effect normal lung development, and will impede the capacity of the lung epithelium to repair itself following injury. To test this hypothesis, we propose: 1) to determine whether expression of the HGF/SF gene is required for normal lung development. We will use embryonic stem (ES) cell and homologous recombination techniques to induce targeted disruption of the murine HGF/SF gene. The lungs of animals homozygous for the defective HGF gene will be examined structurally to determine whether absent HGF gene expression affects normal lung development. If the mutation results in a lethal phenotype, we will produce animals in which targeted disruption can be Induced in a temporally controlled manner. 2) We will determine whether expression of the HGF/SF gene is required for normal repair of alveolar epithelial injury by exposing the animals to normobaric hyperoxia. The capacity for normal alveolar repair will be assessed by examination of lung tissue at various times during and after injury. 3) We will examine the temporal and spatial regulation of the HGF/SF gene during development and after alveolar epithelial injury, by creating a mouse which expresses a lac Z-HGF/SF fusion protein under the control of the native HGF/SF gene regulatory elements. These studies will increase our general understanding of normal lung development and repair, and the role played by HGF/SF in these processes. This knowledge may ultimately lead to improved treatment strategies for the Adult Respiratory Distress Syndrome and other diseases characterized by alveolar epithelial injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CCT-M (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code
Zitnik, R J; Zhang, J; Kashem, M A et al. (1997) The cloning and characterization of a murine secretory leukocyte protease inhibitor cDNA. Biochem Biophys Res Commun 232:687-97