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Cell Rep. 2019 May 7;27(6):1769-1780.e4. doi: 10.1016/j.celrep.2019.04.039.

Endothelial Sash1 Is Required for Lung Maturation through Nitric Oxide Signaling.

Author information

1
Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10(th) Avenue, Vancouver, BC V5Z 1L3, Canada; Department of Experimental Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
2
Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10(th) Avenue, Vancouver, BC V5Z 1L3, Canada.
3
Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10(th) Avenue, Vancouver, BC V5Z 1L3, Canada; Program of Interdisciplinary Oncology, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
4
Terry Fox Laboratory, BC Cancer Agency, 675 West 10(th) Avenue, Vancouver, BC V5Z 1L3, Canada.
5
Department of Integrative Oncology, BC Cancer Research Centre, 675 West 10(th) Avenue, Vancouver, BC V5Z 1L3, Canada.
6
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Terry Fox Laboratory, BC Cancer Agency, 675 West 10(th) Avenue, Vancouver, BC V5Z 1L3, Canada.
7
Department of Pathology, University of British Colombia, Vancouver, BC V6T 2B5, Canada.
8
Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10(th) Avenue, Vancouver, BC V5Z 1L3, Canada; Department of Experimental Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Program of Interdisciplinary Oncology, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Pathology, University of British Colombia, Vancouver, BC V6T 2B5, Canada. Electronic address: akarsan@bcgsc.ca.

Abstract

The sterile alpha motif (SAM) and SRC homology 3 (SH3) domain containing protein 1 (Sash1) acts as a scaffold in TLR4 signaling. We generated Sash1-/- mice, which die in the perinatal period due to respiratory distress. Constitutive or endothelial-restricted Sash1 loss leads to a delay in maturation of alveolar epithelial cells causing reduced surfactant-associated protein synthesis. We show that Sash1 interacts with β-arrestin 1 downstream of the TLR4 pathway to activate Akt and endothelial nitric oxide synthase (eNOS) in microvascular endothelial cells. Generation of nitric oxide downstream of Sash1 in endothelial cells affects alveolar epithelial cells in a cGMP-dependent manner, inducing maturation of alveolar type 1 and 2 cells. Thus, we identify a critical cell nonautonomous function for Sash1 in embryonic development in which endothelial Sash1 regulates alveolar epithelial cell maturation and promotes pulmonary surfactant production through nitric oxide signaling. Lung immaturity is a major cause of respiratory distress and mortality in preterm infants, and these findings identify the endothelium as a potential target for therapy.

KEYWORDS:

Sash1; TLR4; alveolar type 2 cells; endothelium; lung development; nitric oxide; respiratory distress; surfactant; β-arrestin

PMID:
31067462
DOI:
10.1016/j.celrep.2019.04.039
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