title: Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury.
abstract: Laminins are heterotrimeric glycoproteins of the extracellular matrix that are secreted by epithelial cells and which are crucial for the normal structure and function of the basement membrane. We have generated a mouse harboring a conditional knockout of α3 laminin (Lama3(fl/fl)), one of the main laminin subunits in the lung basement membrane. At 60 days after intratracheal treatment of adult Lama3(fl/fl) mice with an adenovirus encoding Cre recombinase (Ad-Cre), the protein abundance of α3 laminin in whole lung homogenates was more than 50% lower than that in control-treated mice, suggesting a relatively long half-life for the protein in the lung. Upon exposure to an injurious ventilation strategy (tidal volume of 35 ml per kg of body weight for 2 hours), the mice with a knockdown of the α3 laminin subunit had less severe injury, as shown by lung mechanics, histology, alveolar capillary permeability and survival when compared with Ad-Null-treated mice. Knockdown of the α3 laminin subunit resulted in evidence of lung inflammation. However, this did not account for their resistance to mechanical ventilation. Rather, the loss of α3 laminin was associated with a significant increase in the collagen content of the lungs. We conclude that the loss of α3 laminin in the alveolar epithelium results in an increase in lung collagen, which confers resistance to mechanical injury.
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Daniela
authors: D
authors: Urich
authors: Jessica L
authors: JL
authors: Eisenberg
authors: Kevin J
authors: KJ
authors: Hamill
authors: Desire
authors: D
authors: Takawira
authors: Sergio E
authors: SE
authors: Chiarella
authors: Saul
authors: S
authors: Soberanes
authors: Angel
authors: A
authors: Gonzalez
authors: Frank
authors: F
authors: Koentgen
authors: Tomas
authors: T
authors: Manghi
authors: Susan B
authors: SB
authors: Hopkinson
authors: Alexander V
authors: AV
authors: Misharin
authors: Harris
authors: H
authors: Perlman
authors: Gokhan M
authors: GM
authors: Mutlu
authors: G R Scott
authors: GR
authors: Budinger
authors: Jonathan C R
authors: JC
authors: Jones
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D007797:Laminin / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011175:Positive-Pressure Respiration; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D055397:Ventilator-Induced Lung Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D024042:Collagen Type I; D007797:Laminin; C095567:laminin alpha 3