Ly-6Chigh inflammatory-monocyte recruitment is regulated by p38 MAPK/MCP-1 activation and promotes ventilator-induced lung injury

Int Immunopharmacol. 2020 Jan:78:106015. doi: 10.1016/j.intimp.2019.106015. Epub 2019 Nov 25.

Abstract

Lymphocyte antigen 6Chigh (Ly-6Chigh) inflammatory monocytes, as novel mononuclear cells in the innate immune system, participate in infectious diseases. In this study, we investigated the potential role of these monocytes in ventilator-induced lung injury (VILI) and the possible mechanism involved in their migration to lung tissue. Our results showed that mechanical ventilation with high tidal volume (HTV) increased the accumulation of Ly-6Chigh inflammatory monocytes in lung tissues and that blocking C‑C chemokine receptor 2 (CCR2) could significantly reduce Ly-6Chigh inflammatory-monocyte migration and attenuate the degree of inflammation of lung tissues. In addition, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) activity could decrease the secretion of monocyte chemoattractant protein 1 (MCP-1), which in turn decreased the migration of Ly-6Chigh inflammatory monocytes into lung tissue. We also demonstrated that high ventilation caused Ly-6Chigh inflammatory monocytes in the bone marrow to migrate into and aggregate in the lungs, creating inflammation, and that the mechanism was quite different from that of infectious diseases. Ly-6Chigh inflammatory monocytes might play a pro-inflammatory role in VILI, and blocking their infiltration into lung tissue might become a new target for the treatment of this injury.

Keywords: Ly-6C(high) inflammatory monocytes; Ventilator-induced lung injury; p38 MAPK/MCP-1 pathway.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Antigens, Ly / metabolism
  • Benzoxazines / pharmacology
  • Benzoxazines / therapeutic use
  • Bone Marrow / immunology
  • Bone Marrow / pathology
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Chemokine CCL2 / metabolism*
  • Disease Models, Animal
  • Humans
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Lung / cytology
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Receptors, CCR2 / antagonists & inhibitors
  • Receptors, CCR2 / metabolism
  • Spiro Compounds / pharmacology
  • Spiro Compounds / therapeutic use
  • Tidal Volume
  • Ventilator-Induced Lung Injury / diagnosis
  • Ventilator-Induced Lung Injury / drug therapy
  • Ventilator-Induced Lung Injury / immunology*
  • Ventilator-Induced Lung Injury / pathology
  • Ventilators, Mechanical / adverse effects
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antigens, Ly
  • Benzoxazines
  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Imidazoles
  • Pyridines
  • RS 504393
  • Receptors, CCR2
  • Spiro Compounds
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580