title: Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice.
abstract: Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice (Eln(+/-)) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type (Eln(+/+)) and Eln(+/-) littermates at baseline and after MV with air for 8-24 h. Lungs of unventilated Eln(+/-) mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln(+/+) pups. Eln(+/-) lungs contained fewer capillaries than Eln(+/+) lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln(+/+) neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln(+/-) mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln(+/-) than in Eln(+/+) pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln(+/-) compared with Eln(+/+) mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln(+/+) and Eln(+/-) mice. Paucity of lung capillaries in Eln(+/-) newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln(+/-) mice.
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California; Comprehensive Pneumology Center, Ludwig-Maximilian University, Munich, Germany; and.
authors.forename: Anne
authors.initials: A
authors.lastname: Hilgendorff
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Kakoli
authors.initials: K
authors.lastname: Parai
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Robert
authors.initials: R
authors.lastname: Ertsey
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Edwin
authors.initials: E
authors.lastname: Navarro
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Noopur
authors.initials: N
authors.lastname: Jain
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Francis
authors.initials: F
authors.lastname: Carandang
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Joanna
authors.initials: J
authors.lastname: Peterson
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Lucia
authors.initials: L
authors.lastname: Mokres
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Carlos
authors.initials: C
authors.lastname: Milla
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Preuss
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Miguel Alejandre
authors.initials: MA
authors.lastname: Alcazar
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Suleman
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Juliet
authors.initials: J
authors.lastname: Masumi
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Nancy
authors.initials: N
authors.lastname: Ferreira-Tojais
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Sana
authors.initials: S
authors.lastname: Mujahid
authors.affiliation: Department of Biochemistry, University of Texas, Tyler, Texas.
authors.forename: Barry
authors.initials: B
authors.lastname: Starcher
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California;
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California; rbland@stanford.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Bland
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D004549:Elastin / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D057895:Haploinsufficiency; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology; D010196:Pancreatic Elastase / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000473:pathology / Q000503:physiopathology; D012121:Respiration, Artificial; D066253:Vascular Remodeling; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D004549:Elastin; D036341:Intercellular Signaling Peptides and Proteins; D010196:Pancreatic Elastase; D000099152:Cadherin 5
keywords: collagen; elastic fiber formation; extracellular matrix components; lung cell apoptosis; lung growth and development; lysyl oxidase and fibrillins; pulmonary capillaries