Abstract
BackgroundHeparin has been shown to modify fundamental biologic processes ranging from blood coagulation and cell proliferation to fibrogenesis and asthma. The goal of this study was to identify specific or broad biologic responses of the rat lung to intratracheal instillation of heparin by targeted proteomic analysis.MethodsRats were given either aerosolized 500 μg heparin in 250 μl saline or saline alone. Lungs were harvested at 0, 24, or 96 hours post-treatment and isolated proteins analyzed by two-dimensional gel electrophoresis. Proteins which increased and decreased significantly in treated groups above controls were then selected for identification by mass spectrometry.ResultsAlthough heparin treatments resulted in a general reduction in cytosolic protein expression, there were significant increases within members of discrete groups of proteins. At 24 hours, proteins which function in cytoskeletal organization and in calcium signaling were up-regulated between 2- and 27-fold above baseline and untreated controls. Increased proteins include annexins V and VI, septin 2, capping G protein, actin-related protein 3, moesin, RhoGDP dissociation inhibitor, and calcyclin. A group of proteins relating to immune response and tumor suppressor function were either up-regulated (tumor suppressor p30/hyaluronic acid binding protein-1, Parkinson disease protein 7, proteosome 28 subunit/interferon-γ inducible protein, and proteosome subunit macropain α-1) or strongly down-regulated (transgelin). At 96 hours, most proteins that had increased at 24 hours remained elevated but to a much lesser degree.ConclusionThese cumulative observations demonstrate that whole lung heparin treatment results in significant up-regulation of selected groups of proteins, primarily those related to cytoskeletal reorganization and immune function, which may prove to be relevant biomarkers useful in analysis of lung exposures/treatments as well as in system biology studies.
Highlights
Heparin has been shown to modify fundamental biologic processes ranging from blood coagulation and cell proliferation to fibrogenesis and asthma
These cumulative observations support the notion that heparin treatment of whole lung as in the present study and as has been previously reported in cell cultures [19,21] results in calcium influx into lung cell cytosolic compartments and triggers significant increases in expression or relocation of selected groups of proteins related to cytoskeletal reorganization and immune function
Alterations of the rat lung proteome in response to heparin are detailed for the first time
Summary
Heparin has been shown to modify fundamental biologic processes ranging from blood coagulation and cell proliferation to fibrogenesis and asthma. Heparin's anti-coagulant activity is well established, but more recently it has been appreciated for its antiproliferative effects, as noted above, which can prevent lung damage due to hypoxia [11], bleomycin-induced fibrosis [13] and cancer [14] These effects have been shown to be a function of the sulfated nature of these molecules, as desulfated or otherwise modified forms are not as effective [46,9,10]. Heparin has been shown clinically to inhibit specific asthmatic responses in humans and prevent bronchoconstriction in exercise-induced asthma by mechanisms not fully understood [15,16,17] It has been used experimentally as a model component of extracellular matrix and cell surface shedding [4,5,6,16]
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