Lung defects in neonatal and adult stromal-derived factor-1 conditional knockout mice.
Stromal-derived factor (SDF)-1/CXCL12 is a cytokine that is involved in organogenesis, hematopoiesis, chemoattraction, and wound healing. An SDF-1 knockout mouse (SDF-1(-/-)) has provided important insights into the role of SDF-1 in fetal development. Because the SDF-1 knockout is lethal in the perinatal period, we have created a conditional SDF-1 knockout mouse. In the present study, we induced conditionally knocked out SDF-1 in neonatal mice and found that lung development was compromised; neonatal lungs showed increased alveolar airspace and abnormal ultrastructure. Conditional knockout of SDF-1 in adult mice resulted in an emphysemic morphology, with increased alveolar airspace and thickened alveolar septa. Fluorescence angiography showed pulmonary vessel hyperdilation. To determine whether the hyperdilation involved nitric oxide, we inhibited endothelial nitric oxide synthase (eNOS) with N (G)-nitro-L- arginine methyl ester. This resulted in the inhibition of pulmonary vessel hyperdilation. Western blot results showed increased phosphorylation of eNOS in our induced SDF-1 knockout mice, indicating that eNOS is normally repressed in the presence of SDF-1, and that activation of eNOS contributes to pulmonary pathology. Thus, a conditional knockout mouse has been successfully created for SDF-1; initial characterization indicates that SDF-1 is intimately involved in lung development and physiology.
Chen
Wen-Cheng
WC
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-Tou, Taipei 11221, Taiwan.
Tzeng
Yi-Shiuan
YS
Li
Hung
H
Tien
Wei-Sheng
WS
Tsai
Ying-Chieh
YC
D000818:Animals; D000831:Animals, Newborn; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000254:growth & development / Q000378:metabolism*; D014664:Vasodilation / Q000235:genetics
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D004791:Enzyme Inhibitors; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester