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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
Cathepsin S deficiency confers protection from neonatal hyperoxia-induced lung injury
Hiroshi Hirakawa1, Richard A Pierce, Gulbin Bingol-Karakoc
1Division of Newborn Medicine, Brigham and Women's Hospital, Thorn 1019, 75 Francis Street, Boston, MA 02115, USA.
Insights
Cathepsin S deficiency protects newborn mice from lung injury caused by high oxygen exposure. This suggests targeting cathepsin S may be a novel therapeutic strategy for bronchopulmonary dysplasia.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Biochemistry
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants, impacting lung function and neurodevelopment.
- Elastolytic proteases, including cathepsin S (cat S), are implicated in BPD pathogenesis.
- Elevated cat S levels and activity were observed in a baboon model of BPD.
Purpose of the Study:
- To determine if a lack of cat S affects the severity of hyperoxia-induced lung injury in neonatal mice.
- Investigate the role of cat S in the development of neonatal lung disease.
Main Methods:
- Newborn wild-type and cat S-deficient mice were exposed to 80% oxygen for 14 days.
- Histologic, morphometric, and biochemical analyses of lung tissue and bronchoalveolar lavage fluid were performed.
- Lung elastin, myofibroblast distribution, and hydroxyproline content were assessed.
Main Results:
- Cat S-deficient mice showed protection from hyperoxia-induced growth restriction and improved alveolarization.
- Reduced septal wall thickness, fewer macrophages, and lower protein levels were observed in cat S-deficient mice.
- Myofibroblast presence and lung hydroxyproline content were significantly lower in cat S-deficient mice exposed to hyperoxia.
Conclusions:
- Cathepsin S deficiency ameliorates alveolar development and reduces inflammation and fibrosis in a mouse model of neonatal lung injury.
- Targeting cat S may offer a therapeutic approach for preventing or treating bronchopulmonary dysplasia.
Rationale:
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.
Objectives:
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.
Measurements And Main 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.