Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 49, Issue 4, Pages 619-626Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2012-0440OC
Keywords
hemolytic disease; NF-kappa B; Toll-like receptors; MyD88; sickle-cell disease
Funding
- American Physiological Society
- National Institutes of Health [5P01HL014985-38]
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The release of hemoglobin (Hb) with hemolysis causes vascular dysfunction. New evidence implicates Hb-induced NF-kappa B and hypoxia inducible factor (HIF) activation, which may be under the control of a Toll-like receptor (TLR)-signaling pathway. Nearly all TLR-signaling pathways activate the myeloid differentiation primary response gene-88 (MyD88) that regulates NF-kappa B. We hypothesized that the differing transition states of Hb influence endothelial cell permeability via NF-kappa B activation and HIF regulation through a MyD88-dependent pathway. In cultured human dermal microvascular endothelial cells (HMECs-1), we examined the effects of Hb in the ferrous (HbFe(2+)), ferric (HbFe(3+)), and ferryl (HbFe(4+)) transition states on NF-kappa B and HIF activity, HIF-1 alpha and HIF-2 alpha mRNA up-regulation, and monolayer permeability, in the presence or absence of TLR4, MyD88, NF-kappa B, or HIF inhibition, as well as superoxide dismutase (SOD) and catalase. Our data showed that cell-free Hb, in each transition state, induced NF-kappa B and HIF activity, up-regulated HIF-1 alpha and HIF-2amRNA, and increased HMEC-1 permeability. The blockade of either MyD88 or NF-kappa B, but not TLR4, attenuated Hb-induced HIF activity, the up-regulation HIF-1 and HIF-2 alpha mRNA, and HMEC-1 permeability. The inhibition of HIF activity exerted less of an effect on Hb-induced monolayer permeability. Moreover, SOD and catalase attenuated NF-kappa B, HIF activity, and monolayer permeability. Our results demonstrate that Hb-induced NF-kappa B and HIF are regulated by two mechanisms, either MyD88 activation or Hb transition state-induced ROS formation, that influence HMEC-1 permeability.
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