Emphysema: an autoimmune vascular disease?
We propose that an endogenous maintenance program controls lung cell turnover, apoptosis, and tissue repair, and that emphysema is a manifestation of the breakdown of the lung structure maintenance program. Emphysema can be induced experimentally in rats by three methods: blockade of vascular endothelial growth factor receptors using SU5416, a small molecule-tyrosine kinase inhibitor; methylprednisolone, which activates matrix metalloproteinase-9 and decreases Akt phosphorylation; and antibodies directed against endothelial cells (autoimmune emphysema). SU5416-induced emphysema is associated with lung induction of cytochrome P450 and oxidant stress, and a superoxide dismutase mimetic or N-acetylcysteine prevents this form of emphysema. A broad-spectrum metalloproteinase inhibitor prevents methylprednisolone-induced emphysema and, finally, autoimmune emphysema is associated with increased lung tissue metalloproteinase-9 expression and alveolar septal cell apoptosis. Athymic rats, which lack CD4+ T cells, are protected against autoimmune emphysema, whereas adoptive transfer of CD4+ T cells causes autoimmune emphysema in naive adult rats. It appears that vascular endothelial growth factor and signaling via its receptors plays a central role in the lung structural maintenance program, and oxidative stress, proteolysis, and apoptosis may coincide in the moment of lung cell destruction. Interestingly, the methylprednisolone model illustrates that inflammation is not necessary for the development of emphysema.
Voelkel
Norbert
N
COPD Center, Pulmonary and Critical Care Medicine Division, 4200 East Ninth Avenue, C272, Denver, CO 80262, USA. norbert.voelkel@uchsc.edu
Taraseviciene-Stewart
Laima
L
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology*; D049109:Cell Proliferation; D016228:Endothelial Growth Factors / Q000502:physiology*; D005938:Glucocorticoids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008775:Methylprednisolone / Q000494:pharmacology; D018384:Oxidative Stress / Q000276:immunology / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011656:Pulmonary Emphysema / Q000276:immunology* / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
D001323:Autoantibodies; D016228:Endothelial Growth Factors; D005938:Glucocorticoids; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C116890:Semaxinib; D040262:Receptors, Vascular Endothelial Growth Factor; D008775:Methylprednisolone