Browsing by Subject "Interstitial fibrosis"

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    Ceramide and sphingosine-1 phosphate in COPD lungs
    (BMJ, 2021-01-29) Berdyshev, Evgeny V.; Serban, Karina A.; Schweitzer, Kelly S.; Bronova, Irina A.; Mikosz, Andrew; Petrache, Irina; Medicine, School of Medicine
    Studies of chronic obstructive pulmonary disease (COPD) using animal models and patient plasma indicate dysregulation of sphingolipid metabolism, but data in COPD lungs are sparse. Mass spectrometric and immunostaining measurements of lungs from 69 COPD, 16 smokers without COPD and 13 subjects with interstitial lung disease identified decoupling of lung ceramide and sphingosine-1 phosphate (S1P) levels and decreased sphingosine kinase-1 (SphK1) activity in COPD. The correlation of ceramide abundance in distal COPD lungs with apoptosis and the inverse correlation between SphK1 activity and presence of emphysema suggest that disruption of ceramide-to-S1P metabolism is an important determinant of emphysema phenotype in COPD.
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    Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
    (SpringerNature, 2016-12-14) Yang, Jin; Savvatis, Konstantinos; Kang, Jong Seok; Fan, Peidong; Zhong, Hongyan; Schwartz, Karen; Barry, Vivian; Mikels-Vigdal, Amanda; Karpinski, Serge; Kornyeyev, Dmytro; Adamkewicz, Joanne; Feng, Xuhui; Zhou, Qiong; Shang, Ching; Kumar, Praveen; Phan, Dillon; Kasner, Mario; Lopez, Begona; Diez, Javier; Wright, Keith C.; Kovacs, Roxanne L.; Chen, Peng-Sheng; Quertermous, Thomas; Smith, Victoria; Yao, Lina; Tschope, Carsten; Chang, Ching-Pin; Department of Medicine, IU School of Medicine
    Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.