Inflammatory cytokines, goblet cell hyperplasia and altered lung mechanics in Lgl1+/- mice.
BACKGROUND
Neonatal lung injury, a leading cause of morbidity in prematurely born infants, has been associated with arrested alveolar development and is often accompanied by goblet cell hyperplasia. Genes that regulate alveolarization and inflammation are likely to contribute to susceptibility to neonatal lung injury. We previously cloned Lgl1, a developmentally regulated secreted glycoprotein in the lung. In rat, O2 toxicity caused reduced levels of Lgl1, which normalized during recovery. We report here on the generation of an Lgl1 knockout mouse in order to determine whether deficiency of Lgl1 is associated with arrested alveolarization and contributes to neonatal lung injury.


METHODS
An Lgl1 knockout mouse was generated by introduction of a neomycin cassette in exon 2 of the Lgl1 gene. To evaluate the pulmonary phenotype of Lgl1+/- mice, we assessed lung morphology, Lgl1 RNA and protein, elastin fibers and lung function. We also analyzed tracheal goblet cells, and expression of mucin, interleukin (IL)-4 and IL-13 as markers of inflammation.


RESULTS
Absence of Lgl1 was lethal prior to lung formation. Postnatal Lgl1+/- lungs displayed delayed histological maturation, goblet cell hyperplasia, fragmented elastin fibers, and elevated expression of TH2 cytokines (IL-4 and IL-13). At one month of age, reduced expression of Lgl1 was associated with elevated tropoelastin expression and altered pulmonary mechanics.


CONCLUSIONS
Our findings confirm that Lgl1 is essential for viability and is required for developmental processes that precede lung formation. Lgl1+/- mice display a complex phenotype characterized by delayed histological maturation, features of inflammation in the post-natal period and altered lung mechanics at maturity. Lgl1 haploinsufficiency may contribute to lung disease in prematurity and to increased risk for late-onset respiratory disease.
Lan
Jie
J
McGill University, Montreal Children's Hospital Research Institute Montreal, Quebec, H3Z2Z3, Canada. jack_lan@hotmail.com
Ribeiro
Leslie
L
Mandeville
Isabel
I
Nadeau
Katia
K
Bao
Tim
T
Cornejo
Salomon
S
Sweezey
Neil B
NB
Kaplan
Feige
F
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D020397:Goblet Cells / Q000378:metabolism*; D007155:Immunologic Factors / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D055370:Lung Injury; D051379:Mice; D018345:Mice, Knockout / Q000378:metabolism*; D015656:Respiratory Mechanics
D016207:Cytokines; D006023:Glycoproteins; D007155:Immunologic Factors; C524369:LGL1 protein, mouse