Doxycycline treatment prevents alveolar destruction in VEGF-deficient mouse lung.
In vivo lung-targeted VEGF gene inactivation results in pulmonary cell apoptosis, airspace enlargement, and increased lung compliance consistent with an emphysema-like phenotype. The predominant hypothesis for the cause of lung destruction in emphysema is an imbalance between active lung protease and anti-protease molecules. Therefore, we investigated the role of protease (e.g., matrix metalloproteinases--MMPs) and anti-protease (e.g., tissue inhibitors of metalloproteinases--TIMPs) expression in contributing to the lung structural remodeling observed in pulmonary-VEGF-deficient mice. VEGFLoxP mice instilled through the trachea with an adeno-associated virus expressing Cre recombinase (AAV/Cre) manifest airspace enlargement and a greater (P < 0.05) mean linear intercept (MLI: 44.2 +/- 4.2 microm) compared to mice instilled with a control virus expressing LacZ (31.3 +/- 2.5 microm). Airspace enlargement was prevented by the continuous administration of the general MMP inhibitor, doxycycline (Dox) (Cre + Dox: 32.6 +/- 2.5 microm), and MLI values were not different from either control (LacZ + Dox: 30.5 +/- 1.2 microm). In situ magnetic resonance imaging of VEGF gene inactivated mouse lungs revealed uneven inflation, residual trapped gas volumes upon oxygen absorption deflation/re-inflation, and loss of parenchymal structure; effects that were largely prevented by Dox. Five weeks after AAV/Cre infection Western blot revealed a 9.9-fold increase in pulmonary MMP-3, and 2-fold increases in MMP-9 and TIMP-2. However, the increase in MMP-3 was prevented by Dox administration and was associated with a 2-fold increase in serpin b5 (Maspin) expression. These results suggest that doxycycline treatment largely prevents the aberrant lung remodeling response observed in VEGF-deficient mouse lungs and is associated with changes in protease and anti-protease expression.
Rossiter
Harry B
HB
Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK.
Scadeng
Miriam
M
Tang
Kechun
K
Wagner
Peter D
PD
Breen
Ellen C
EC
D000818:Animals; D004318:Doxycycline / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D008168:Lung / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D008279:Magnetic Resonance Imaging; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D051379:Mice; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D015843:Serpins; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D042442:Vascular Endothelial Growth Factors / Q000172:deficiency*
C085344:SERPIN-B5; D015843:Serpins; D019714:Tissue Inhibitor of Metalloproteinases; D042442:Vascular Endothelial Growth Factors; D019716:Tissue Inhibitor of Metalloproteinase-2; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline