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Modulation of neutrophil apoptosis by murine pulmonary microvascular endothelial cell inducible nitric oxide synthase

Lefeng Wang1, Sanjay Mehta, Chris Gillis

  • 1Centre for Critical Illness Research, Lawson Health Research Institute, London Health Sciences Center, London, Ontario, Canada.

Biochemical and Biophysical Research Communications
|September 14, 2010
PubMed

Insights

Pulmonary microvascular endothelial cell inducible nitric oxide synthase (iNOS) inhibits neutrophil apoptosis during migration, a key factor in acute lung injury (ALI). Neutrophil iNOS does not affect this process, highlighting PMEC iNOS

Area of Science:

  • Immunology
  • Cell Biology
  • Pulmonary Medicine

Background:

  • Neutrophils are key players in acute lung injury (ALI) pathogenesis.
  • Neutrophil migration across pulmonary microvascular endothelial cells (PMEC) delays apoptosis, promoting ALI.
  • The role of inducible nitric oxide synthase (iNOS) in neutrophils and PMECs in modulating neutrophil apoptosis during ALI is unclear.

Purpose of the Study:

  • To investigate the distinct roles of neutrophil and PMEC iNOS in regulating neutrophil apoptosis during trans-PMEC migration.
  • To determine if PMEC iNOS-dependent inhibition of neutrophil apoptosis involves caspase-3 activity.

Main Methods:

  • Quantification of neutrophil apoptosis using microscopy and FACS annexin-V binding.
  • Assessment of apoptosis in wild-type and iNOS-/- neutrophils.
  • Murine model of ALI involving broncho-alveolar lavage (BAL) and ex vivo culture.
  • Analysis of neutrophil migration across iNOS+/+ and iNOS-/- PMECs.

Main Results:

  • Neutrophils from iNOS-/- mice exhibited significantly higher apoptosis rates ex vivo compared to wild-type neutrophils.
  • Trans-PMEC migration inhibited neutrophil apoptosis only when occurring across iNOS+/+ PMECs, not iNOS-/- PMECs.
  • PMEC iNOS-dependent inhibition of neutrophil apoptosis was observed irrespective of neutrophil caspase-3 activity.

Conclusions:

  • Pulmonary microvascular endothelial cell (PMEC) iNOS, not neutrophil iNOS, significantly inhibits neutrophil apoptosis during trans-PMEC migration.
  • This inhibitory effect is independent of neutrophil caspase-3 activity.
  • Findings suggest a novel mechanism in ALI pathogenesis and warrant further investigation in human neutrophils and ALI.

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