semaxinib and Emphysema

Topics: Animals; Emphysema; Hypertension, Pulmonary; Hypoxia; Indoles; Pyrroles; Rats; Rats, Sprague-Dawley

Topics: Adult; Animals; Emphysema; Hypertension, Pulmonary; Hypoxia; Indoles; Pulmonary Emphysema; Pyrroles; Rats; Receptors, Vascular Endothelial Growth Factor

Topics: Animals; Emphysema; Hypertension, Pulmonary; Hypoxia; Indoles; Phenotype; Pulmonary Arterial Hypertension; Pyrroles; Rats

Topics: Animals; Emphysema; Hypertension, Pulmonary; Hypoxia; Indoles; Phenotype; Pulmonary Arterial Hypertension; Pyrroles; Rats

Topics: Animals; Apoptosis; Azo Compounds; Cell Hypoxia; Disease Models, Animal; Emphysema; Endothelial Cells; Humans; Hypertension, Pulmonary; Indoles; Mice; Protein Kinase Inhibitors; Pyrazoles; Pyrroles; Rats; Receptors, Aryl Hydrocarbon; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Efficient clearance of apoptotic cells from the lung by alveolar macrophages is important for the maintenance of tissue structure and function. Lung tissue from humans with emphysema contains increased numbers of apoptotic cells and decreased levels of vascular endothelial growth factor (VEGF). Mice treated with VEGF receptor inhibitors have increased numbers of apoptotic cells and develop emphysema. We hypothesized that VEGF regulates apoptotic cell clearance by alveolar macrophages (AM) via its interaction with VEGF receptor 1 (VEGF R1). Our data show that the uptake of apoptotic cells by murine AMs and human monocyte-derived macrophages is inhibited by depletion of VEGF and that VEGF activates Rac1. Antibody blockade or pharmacological inhibition of VEGF R1 activity also decreased apoptotic cell uptake ex vivo. Conversely, overexpression of VEGF significantly enhanced apoptotic cell uptake by AMs in vivo. These results indicate that VEGF serves a positive regulatory role via its interaction with VEGF R1 to activate Rac1 and enhance AM apoptotic cell clearance.

Topics: Animals; Antibodies, Monoclonal; Apoptosis; Cell Line; Doxycycline; Emphysema; Humans; Indoles; Jurkat Cells; Lung; Macrophages, Alveolar; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pyrroles; rac1 GTP-Binding Protein; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Transforming growth factor (TGF)-beta1 has been reported to cause endothelial cell apoptosis. However, conflicting data have also demonstrated that TGF-beta1 promotes endothelial cell survival. In this study, the effect of TGF-beta1 on apoptosis of cultured bovine pulmonary artery endothelial cells (PAEC) induced by multiple stimuli was investigated. TGF-beta1 protected against apoptosis of bovine PAEC induced by serum deprivation or the VEGF receptor inhibitor SU-5416, but not by UV light exposure or TNFalpha. Neither caspase-8 nor caspase-12 was activated by serum deprivation or the VEGF receptor blocker. However, blockade of VEGF receptors activated caspase-9, an effect that was abolished by TGF-beta1. Furthermore, serum deprivation and inhibition of VEGF receptors significantly decreased the protein level of Bcl-2, an effect that was also abrogated by TGF-beta1. In addition, the baseline level of Bcl-2 was enhanced by TGF-beta1 and reduced by inhibition of activin receptor-like kinase 5 (ALK5), a TGF-beta1 type I receptor. Furthermore, inhibition of ALK5 caused apoptosis of bovine PAEC. These results suggest that TGF-beta1 signaling is critical for maintenance of bovine PAEC survival. Finally, the protective effects of TGF-beta1 on bovine PAEC apoptosis and Bcl-2 reduction were abolished by ALK5 inhibition, but not by inhibition of non-SMAD signaling pathways. Also, TGF-beta1 activated SMAD2 and SMAD1/5, an effect that was abolished by ALK5 inhibition. The results of this study suggest that TGF-beta1 protects against bovine PAEC apoptosis, possibly through ALK5-mediated Bcl-2 induction and subsequent inhibition of the mitochondria-mediated intrinsic pathway of apoptosis. Understanding the mechanism by which TGF-beta1 promotes endothelial cell survival may provide a better treatment for apoptosis-dependent vascular diseases, such as emphysema.

Topics: Animals; Apoptosis; Caspase 12; Caspase 8; Cattle; Cell Survival; Emphysema; Endothelial Cells; Enzyme Activation; Humans; Indoles; Mitochondria; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Pulmonary Artery; Pyrroles; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Smad Proteins; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Ultraviolet Rays

Administration of the VEGF receptor blocker SU5416 to rats causes alveolar septal cell apoptosis and emphysema; both can be prevented by a superoxide dismutase mimetic. Here we show that SU5416 induces the expression of heme oxygenase-1 in the lung tissue and that administration of antioxidant N-acetyl-l-cysteine protects alveolar septal cells against apoptosis, as demonstrated by caspase-3 lung immunohistochemistry, and against emphysema.

Topics: Acetylcysteine; Animals; Apoptosis; Disease Models, Animal; Dose-Response Relationship, Drug; Emphysema; Heme Oxygenase-1; Hypertrophy, Right Ventricular; Indoles; Lung; Male; Oxidative Stress; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Vascular Endothelial Growth Factor