Cigarette smoke induction of s100a9 contributes to chronic obstructive pulmonary disease

Christopher Railwah, Alnardo Lora, Kanza Zahid, Hannah Goldenberg, Michael Campos, Anne Wyman, Bakr Jundi, Magdalena Ploszaj, Melissa Rivas, Abdoulaye Dabo, Susan M. Majka, Robert Foronjy, Mohamed El Gazzar, Patrick Geraghty

Research output: Contribution to journalArticlepeer-review

Abstract

S100 calcium-binding protein A9 (S100A9) is elevated in plasma and bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9- mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared with in young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9 -/- mice or mice administered paquinimod were exposed to chronic cigarette smoke. S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and forced expiratory volume in 0.05 s/forced vital capacity, compared with age-matched wild-type or vehicleadministered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK and c-RAF phosphorylation, matrix metalloproteinase- 3 (MMP-3), matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte- derived chemokine (KC) release into the airways. Paquinimod administered to nonsmoked, aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor LY3214996 or the c-RAF inhibitor GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing Toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), or extracellular matrix metalloproteinase inducer (EMMPRIN) prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke-induced and age-related COPD.

Original languageEnglish (US)
Pages (from-to)L1021-L1035
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume319
Issue number6
DOIs
StatePublished - Dec 18 2020

Keywords

  • Aging
  • Cigarette smoke
  • Kinase
  • Pulmonary function
  • S100A9

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Fingerprint Dive into the research topics of 'Cigarette smoke induction of s100a9 contributes to chronic obstructive pulmonary disease'. Together they form a unique fingerprint.

Cite this