Zinc salicylate reduces airway smooth muscle cells remodelling by blocking mTOR and activating p21(Waf1/Cip1)

Lei Fang; Michael Roth; Chong Teck S'ng; Michael Tamm; Bo Han; Ba Xuan Hoang

doi:10.1016/j.jnutbio.2020.108563

Zinc salicylate reduces airway smooth muscle cells remodelling by blocking mTOR and activating p21^(Waf1/Cip1)

J Nutr Biochem. 2021 Mar:89:108563. doi: 10.1016/j.jnutbio.2020.108563. Epub 2020 Dec 14.

Authors

Lei Fang¹, Michael Roth², Chong Teck S'ng³, Michael Tamm¹, Bo Han⁴, Ba Xuan Hoang⁴

Affiliations

¹ Pulmonary Cell Research/Pneumology, Department of Biomedicine/Internal Medicine, University and University Hospital Basel, Basel, Switzerland.
² Pulmonary Cell Research/Pneumology, Department of Biomedicine/Internal Medicine, University and University Hospital Basel, Basel, Switzerland. Electronic address: michael.roth@usb.ch.
³ PersCellMed S'ng, Sissach, Switzerland.
⁴ Cordoba-Nimni Tissue Engineering and Drug Discovery Lab, Department of Surgery, University of Southern California, Los Angeles, California.

PMID: 33326841
DOI: 10.1016/j.jnutbio.2020.108563

Abstract

Asthma is characterized by chronic inflammation and tissue remodeling of the airways. Remodeling is resistant to pharmaceutical therapies. This study investigated the effect of zinc salicylate-methylsulfonylmethane (Zn-Sal-MSM) compared to zinc salicylate (Zn-Sal), or sodium salicylate (Na-Sal), or zinc chloride (ZnCl₂) on remodeling parameters of human airway smooth muscle cells (ASMC). Human ASMC obtained from asthma patients (n=7) and non-asthma controls (n=7) were treated with one of the reagents. Cell proliferation and viability was determined by direct cell counts and MTT assay. The expression of and phosphorylation proteins was determined by Western-blotting, ELISA, immunofluorescence, and mass spectrometry. Extracellular matrix deposition by ELISA. Zn-Sal-MSM, Zn-Sal and Na-Sal (0.1-100 µg/mL) significantly reduced PDGF-BB-induced proliferation in a concentration dependent manner, while ZnCl₂ was toxic. The reduced proliferation correlated with increased expression of the cell cycle inhibitor p21^(Waf1/Cip1), and reduced activity of Akt, p70S6K, and Erk1/2. Zn-Sal-MSM, Zn-Sal, but not Na-Sal reduced the deposition of fibronectin and collagen type-I. Furthermore, Zn-Sal-MSM reduced the mitochondria specific COX4 expression. Mass spectrometry indicated that Zn-Sal-MSM modified the expression of several signaling proteins and zinc-dependent enzymes. In conclusion, Zn-Sal-MSM and Zn-Sal potentially prevent airway wall remodeling in asthma by inhibition of both the Erk1/2 and mTOR signaling pathways.

Keywords: Airway smooth muscle cell remodeling; Asthma; COPD; Zinc salicylate.

MeSH terms

Adult
Aged
Airway Remodeling / drug effects*
Animals
Asthma / drug therapy*
Asthma / metabolism
Asthma / pathology
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Collagen Type I / metabolism
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
Extracellular Matrix / drug effects
Female
Fibronectins / metabolism
Humans
MAP Kinase Signaling System / drug effects
Male
Middle Aged
Myocytes, Smooth Muscle / drug effects*
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Salicylates / pharmacology*
Signal Transduction / drug effects
TOR Serine-Threonine Kinases / metabolism*
Zinc / pharmacology*

Substances

Collagen Type I
Cyclin-Dependent Kinase Inhibitor p21
Fibronectins
Salicylates
MTOR protein, human
Ribosomal Protein S6 Kinases, 70-kDa
TOR Serine-Threonine Kinases
Zinc