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Alveolar macrophage inducible nitric oxide synthase-dependent pulmonary microvascular endothelial cell septic barrier

K S Farley1, L F Wang, C Law

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

Microvascular Research
|August 19, 2008
PubMed

Insights

Alveolar macrophage inducible nitric oxide synthase (iNOS) directly increases septic lung vascular permeability. This effect, mediated by peroxynitrite, contributes to acute lung injury.

Area of Science:

  • Pulmonary Medicine
  • Cell Biology
  • Inflammation Research

Background:

  • Inducible nitric oxide synthase (iNOS) in neutrophils and alveolar macrophages (AM) is implicated in septic acute lung injury (ALI).
  • The direct impact of AM iNOS on pulmonary microvascular endothelial cell (PMVEC) permeability during sepsis remains unclear.

Purpose of the Study:

  • To investigate whether AM iNOS directly mediates PMVEC permeability in vitro under septic conditions.
  • To elucidate the role of nitric oxide (NO) and peroxynitrite in this process.

Main Methods:

  • Co-incubation of confluent PMVECs with wild-type (iNOS+/+) versus iNOS-deficient (iNOS-/-) AMs.
  • Assessment of PMVEC permeability using trans-PMVEC albumin flux in response to cytomix stimulation.
  • Pharmacological inhibition of NOS and scavenging of reactive nitrogen/oxygen species.

Main Results:

  • Cytomix significantly increased PMVEC permeability, an effect amplified by iNOS+/+ AMs but not iNOS-/- AMs.
  • AM iNOS-dependent albumin leak was attenuated by iNOS inhibitors and scavengers of NO, superoxide, and peroxynitrite.
  • Exogenous NO did not affect PMVEC permeability, suggesting a role for downstream reactive species.

Conclusions:

  • AM iNOS plays a direct role in septic PMVEC barrier dysfunction.
  • Peroxynitrite is a likely mediator of iNOS-dependent PMVEC permeability in this model.
  • These findings highlight AM iNOS as a potential therapeutic target in septic ALI.

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