ADAMTS18 Deficiency Leads to Pulmonary Hypoplasia and Bronchial Microfibril Accumulation
Tiantian Lu,
Xiaotian Lin,
Yi-Hsuan Pan,
Ning Yang,
Shuai Ye,
Qi Zhang,
Caiyun Wang,
Rui Zhu,
Tianhao Zhang,
Thomas M. Wisniewski,
Zhongwei Cao,
Bi-Sen Ding,
Suying Dang,
Wei Zhang
Affiliations
Tiantian Lu
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Xiaotian Lin
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Yi-Hsuan Pan
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Ning Yang
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Shuai Ye
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Qi Zhang
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Caiyun Wang
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Rui Zhu
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Tianhao Zhang
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
Thomas M. Wisniewski
Departments of Neurology, Pathology and Psychiatry, New York University School of Medicine, New York, NY 10016, USA
Zhongwei Cao
Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
Bi-Sen Ding
Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
Suying Dang
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, China; Corresponding author
Wei Zhang
Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China; Corresponding author
Summary: ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are secreted metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM). In this study, we show that ADAMTS18, produced by the epithelial cells of distal airways and mesenchymal cells in lung apex at early embryonic stages, serves as a morphogen in lung development. ADAMTS18 deficiency leads to reduced number and length of bronchi, tipped lung apexes, and dilated alveoli. These developmental defects worsen lipopolysaccharide-induced acute lung injury and bleomycin-induced lung fibrosis in adult Adamts18-deficient mice. ADAMTS18 deficiency also causes increased levels of fibrillin1 and fibrillin2, bronchial microfibril accumulation, decreased focal adhesion kinase signaling, and disruption of F-actin organization. Our findings indicate that ECM homeostasis mediated by ADAMTS18 is pivotal in airway branching morphogenesis.
