Strain variation in response to lung ischemia: role of MMP-12.
BACKGROUND
Systemic neovascularization of the lung during chronic ischemia has been observed in all mammals studied. However, the proteins that orchestrate the complex interaction of new vessel growth and tunneling through lung tissue matrix have not been described. Although previous work has demonstrated the CXC chemokines are essential growth factors in the process of angiogenesis in mice and rats, key matrix proteins have not been identified.


METHODS
Since the degradation of chemokines has been shown to be dependent on metalloproteinases (MMP), we first surveyed gene expression patterns (real time RT-PCR) of several lung matrix proteins in DBA/J (D2) mice and C57Bl/6 (B6) mice, strains known to have divergent parenchymal responses in other lung disease models. We studied changes in the time course of MMP-12 activity in D2 and B6 mice. Functional angiogenesis was determined 14 days after the onset of complete left lung ischemia induced by left pulmonary artery ligation (LPAL), using fluorescent microspheres.


RESULTS
Our results confirmed higher levels of MMP-12 gene expression in D2 mice relative to B6, which corresponded to a phenotype of minimal systemic angiogenesis in D2 mice and more robust angiogenesis in B6 mice (p < 0.01). MMP-12 activity decreased over the course of 14 days in B6 mice whereas it increased in D2 mice (p < 0.05). MMP-12 was associated largely with cells expressing the macrophage marker F4/80. Genetic deficiency of MMP-12 resulted in significantly enhanced neovascularization (p < 0.01 from B6).


CONCLUSIONS
Taken together, our results suggest macrophage-derived MMP-12 contributes to angiostasis in the ischemic lung.
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA.
Clarke G
CG
Tankersley
Aigul
A
Moldobaeva
Elizabeth M
EM
Wagner
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D007511:Ischemia / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000276:immunology; D008026:Ligation; D008168:Lung / Q000098:blood supply* / Q000201:enzymology* / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D011651:Pulmonary Artery / Q000601:surgery; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013997:Time Factors
D000943:Antigens, Differentiation; D015415:Biomarkers; C036763:monocyte-macrophage differentiation antigen; D053508:Matrix Metalloproteinase 12