Sabina Marija Janciauskiene, PhD
New anti-inflammatory activities of Alpha-1-Antitrypsin and their role in COPD
Alpha1-Antitrypsin (AAT) is the most abundant serine proteinase inhibitor in human plasma. As an acute phase reactant, tissue and circulating AAT levels increase rapidly in response to inflammation or infection. Until recently, neutralization of serine protease activity, particularly neutrophil elastase and proteinase 3, which are up-regulated in the inflammatory response, was assumed to be the primary function of AAT. Alterations of the AAT molecule that compromise its structure and/or secretion and thereby reduce its level, are known to predispose to diseases. The most convincing example of this phenomenon is the inherited, severe Z AAT deficiency, which predisposes individuals to liver and lung diseases as a consequence of the polymerization of the mutant AAT, which results in dramatically reduced circulating levels of the serpin.
There is now considerable evidence that AAT may exhibit biological activities that are independent of its protease inhibitory function. For instance AAT has been shown to inhibit neutrophil superoxide and chemokine production, to suppress lipopolysaccharide-induced human monocyte activation in vitro, and to reduce bacterial endotoxin and TNF?-induced lethality in vivo. There is also evidence that AAT may have antibacterial activities. Clinical studies provide evidence that augmentation therapy with Prolastin reduces the incidence of lung infections in patients with AAT deficiency-related emphysema. It has been demonstrated that short-term therapy of AAT augmentation not only normalises airway concentrations of AAT, but also reduces levels of the chemoattractant, leukotriene B4. It has also been reported that aerosolized AAT suppresses bacterial proliferation in a rat model of chronic Pseudomonas aeruginosa lung infection.
Together these findings indicate that AAT may not only afford protection against proteolytic injury, but also have anti-microbial activity and down-regulate cellular responses to inflammatory stimuli.
Curriculum Vitae of Sabina Marija Janciauskiene
University Hospital Malmö, Sweden
Associate Professor of Experimental Medicine
|1989 - 1992
Lecturer, Department of Medicine, Kanunas Medical University, Lithuania
|1992 - 1996
Invited Scientist, Department of Medicine, Lund University, Sweden
|1997 - 1998
Teggers postdoctoral fellowship, Lund University, Sweden
|1999 - 2003
Research assistant position from the Swedish Medical Research Council
Associate Professor in Experimental Medicine
Scientist, Head of Research Group at the Department of Clinical Sciences, University Hospital Malmö, Sweden
Member/Chairman of Societies
Member of American Association for the Advancement of Science; European Respiratory Society; American Society for Biochemistry and Molecular Biology; Member of Liver Research Group, Sweden
Since 1987 her research has focused on the serpin family of SERine PRoteinase INhibitors, which play important regulatory roles in vivo. They now recognise that the physicochemical properties of the serpin structure that confer protease inhibitor activity also render these proteins sensitive to post-translational modifications (i.e. oxidation, nitrosylation, inter- or intramolecular interactions and non-specific cleavage). These altered forms of inhibitory serpins are detected in tissues and fluids recovered from inflammatory sites, but the important questions of how they are generated, what their biological activities are, and which of them are directly linked to pathologies and/or may be useful markers for characterisation of disease states, remain to be answered. Her objective is to address this challenge, focusing on the role of native (inhibitory) and post-translationally modified (non-inhibitory) forms of Alpha1-Antitrypsin in obstructive pulmonary disease and Alpha1-antichymotrypsin in neurodegenerative diseases, specifically Alzheimer`s disease.
Dr. Sabina Marija Janciauskiene
Wallenberg lab, Ing 46, Plan 2