Cathepsin S deficiency confers protection from neonatal hyperoxia-induced lung injury.
BACKGROUND
Bronchopulmonary dysplasia (BPD) is a chronic lung disease that adversely affects long-term pulmonary function as well as neurodevelopmental outcomes of preterm infants. Elastolytic proteases have been implicated in the pathogenesis of BPD. Cathepsin S (cat S) is a cysteine protease with potent elastolytic activity. Increased levels and activity of cat S have been detected in a baboon model of BPD.


OBJECTIVE
To investigate whether deficiency of cat S alters the course of hyperoxia-induced neonatal lung injury in mice.


METHODS
Newborn wild-type and cat S-deficient mice were exposed to 80% oxygen for 14 days. Histologic and morphometric analysis were performed and bronchoalveolar lavage protein and cells were analyzed. Lung elastin was assessed by real-time polymerase chain reaction, in situ hybridization, desmosine analysis, and Hart's stain. Distribution of myofibroblasts was analyzed by immunofluorescence. Hydroxyproline content of lung tissues was measured.


RESULTS
Hyperoxia-exposed cat S-deficient mice were protected from growth restriction and had improved alveolarization, decreased septal wall thickness, lower number of macrophages, and lower protein concentration in bronchoalveolar lavage fluid. alpha-Smooth muscle actin-expressing myofibroblasts accounted for at least some of the increased interstitial cellularity in hyperoxia-exposed mouse lungs and were significantly less in cat S-deficient lungs. Lung hydroxyproline content was increased in hyperoxia-exposed wild-type, but not in cat S-deficient lungs. Desmosine content was significantly reduced in both genotypes with hyperoxia.


CONCLUSIONS
Cathepsin S deficiency improves alveolarization, and attenuates macrophage influx and fibroproliferative changes in hyperoxia-induced neonatal mouse lung injury.
Division of Newborn Medicine, Brigham and Women's Hospital, Thorn 1019, 75 Francis Street, Boston, MA 02115, USA.
Hiroshi
H
Hirakawa
Richard A
RA
Pierce
Gulbin
G
Bingol-Karakoc
Cagatay
C
Karaaslan
Meiqian
M
Weng
Guo-Ping
GP
Shi
Ali
A
Saad
Ekkehard
E
Weber
Thomas J
TJ
Mariani
Barry
B
Starcher
Steve D
SD
Shapiro
Sule
S
Cataltepe
D000818:Animals; D000831:Animals, Newborn; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism*; D002403:Cathepsins / Q000172:deficiency* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003895:Desmosine / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D055370:Lung Injury; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D011506:Proteins / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000254:growth & development; D012333:RNA, Messenger / Q000378:metabolism
D011506:Proteins; D012333:RNA, Messenger; D003895:Desmosine; D003094:Collagen; D004549:Elastin; D002403:Cathepsins; C028217:cathepsin S; D006909:Hydroxyproline