Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

Toxicol Appl Pharmacol. 2012 Aug 15;263(1):61-72. doi: 10.1016/j.taap.2012.05.024. Epub 2012 Jun 9.


Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / drug effects
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / prevention & control*
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Bleomycin / pharmacology
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 9 / drug effects
  • DNA Damage / drug effects
  • Dipeptides / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Hydroxamic Acids / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phagocytosis / drug effects*
  • Receptor Protein-Tyrosine Kinases / drug effects
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction


  • Antibiotics, Antineoplastic
  • Dipeptides
  • Hydroxamic Acids
  • N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide
  • Bleomycin
  • Receptor Protein-Tyrosine Kinases
  • Caspase 3
  • Caspase 9
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, mouse