Research

Fu, Jian, Ph.D.

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Contact: jian.fu@uthct.edu

Education:
Ph.D. 2000, Physiology and Biophysics, University of Alabama at Birmingham

Research Interest:
Lung inflammation and injury; Innate Immunity

Current Projects:
Mechanisms of lung inflammation and injury.

Research Overview:
Molecular regulation of endothelial exocytosis in lung inflammation. Weibel-Palade bodies (WPBs) are unique secretory granules in endothelial cells. They are storage pools for pro-inflammatory mediators such as von Willebrand factor (vWF), P-selectin, eotaxin and IL-8. Exocytosis of Weibel-Palade bodies and the resultant release of P-selectin and IL-8 play critical roles in the initiation of inflammation. WPB exocytosis is a rapid event occurring within minutes in response to stimulation by inflammatory mediators such as histamine and thrombin. Yet little is known about the molecular machinery involved in the regulation of WPB exocytosis, representing a critical gap in current understanding of the early-onset endothelial inflammation. Recently, we reported that syntaxin 4, a SNARE (Soluble NSF attachment protein receptor), is expressed in human lung endothelial cells and play important roles in thrombin-induced WPB exocytosis and inflammatory responses. Our studies indicate that syntaxin 4 is an early target of pro-inflammatory signaling in altering the adhesiveness of the plasma membrane for leukocyte recruitment. Therefore, targeting of regulated exocytosis may prevent the development of inflammatory responses in lung endothelial cells. We also demonstrated that VAMP2, a regulator of membrane fusion, co-localized with P-selectin in WPBs. We detected the interactions of VAMP2 with syntaxin 4 and Cdc42, suggesting that coordinated interaction of VAMP2/Syntaxin 4/Cdc42 may regulate the targeted transport of WPB to the plasma membrane and provide a spatial and temporal regulation of lung endothelial exocytosis by pro-inflammatory stimuli. Furthermore, thrombin was able to induce rapid phosphorylation of VAMP2 in endothelial cells, indicating that VAMP2 is a target of pro-inflammatory signaling in endothelial cells. In our studies using a mouse model of endotoxin-induced acute lung injury, syntaxin 4 knockout mice displayed reduced lung inflammation. In our future projects, we will determine the molecular regulation of endothelial exocytosis in both our in vitro cell system and in vivo model of lung inflammation and injury.

Role of LOX-1 in lung inflammation and injury. Lectin-like oxidized LDL receptor-1 (LOX-1), primarily expressed in endothelial cells, is a receptor for oxidized LDL (a well-known mediator of atherogenesis). LOX-1 expression can be regulated by a variety of pro-inflammatory cytokines, oxidized LDL, oxidative stress and shear stress. Increased LOX-1 expression has been observed in atherosclerosis susceptible regions. Deletion of LOX-1 or inhibition of LOX-1 function by a blocking antibody was able to prevent pro-inflammatory, pro-oxidant responses in endothelial cells and reduce atherogenesis in mouse atherosclerosis models. Nevertheless, the function of LOX-1 in lung inflammation and injury remains unknown. Increased blood levels of endotoxin lipopolysaccharide (LPS) due to Gram-negative bacterial infection may lead to acute lung injury (ALI) in sepsis and endotoxemia patients. Despite a significant progress in the study of ALI made during the last decade, the mortality rate remains high among patients with ALI. New therapeutic strategies are needed to reduce the mortality rate associated with the disease. ALI is usually associated with excessive pulmonary inflammation. Even though considerable progress has been made in elucidating the pro-inflammatory mediators that contribute to ALI, it is likely that some of the key mediators remain unidentified. In our previously studies, we reported that LOX-1 was rapidly up-regulated in mouse lung following LPS challenge. Importantly, inhibition of LOX-1 by a functional blocking antibody prevented acute lung inflammation and injury as evidenced by a decrease in the influx of neutrophils into the lung and inhibition of lung vascular leakage. Therefore, our studies indicated that LOX-1 could be a key mediator of lung vascular inflammation and injury in response to LPS challenge. We are in the process to further assess the role of LOX-1 in lung inflammation and injury, and test the potential of LOX-1 as a novel therapeutic target in the prevention and treatment of inflammatory lung injury.

Selected Papers and Abstracts: