Reactive oxygen species and hyaluronidase 2 regulate airway epithelial hyaluronan fragmentation.
Hyaluronidase 2 (Hyal2) is a hyaluronan (HA)-degrading enzyme found intracellularly or/and anchored to the plasma membrane through glycosylphosphatidylinositol (GPI). Normal human bronchial epithelial cells (NHBE) grown at the air-liquid interphase (ALI), treated with PI-specific phospholipase C (PI-PLC), exhibited increased Hyal activity in secretions and decreased protein and activity on the apical membrane, confirming that GPI-anchored Hyal2 is expressed in NHBE cells and it remains active in its soluble form. We have reported that HA degradation was mediated by reactive oxygen species (ROS) in human airways. Here we show that ROS increase Hyal2 expression and activity in NHBE cells and that the p38MAPK signaling pathway is involved in this effect. Hyal2 induction was confirmed by using small interfering RNA (siRNA) expressing lentivirus. These in vitro findings correlated in vivo with smokers, where increased Hyal2 immunoreactivity in the epithelium was associated with augmented levels of HA and the appearance of low molecular mass HA species in bronchial secretions. In summary, this work provides evidence that ROS induce Hyal2, suggesting that Hyal2 is likely responsible for the sustained HA fragmentation in the airway lumen observed in inflammatory conditions associated with oxidative stress.
Monzon
Maria E
ME
Division of Pulmonary Critical Care Sleep Medicine, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA. mmonzonmedina@med.miami.edu
Fregien
Nevis
N
Schmid
Nathalie
N
Falcon
Nieves S
NS
Campos
Michael
M
Casalino-Matsuda
S Marina
SM
Forteza
Rosanna Malbran
RM
D000951:Antigens, Neoplasm / Q000378:metabolism*; D002478:Cells, Cultured; D017261:Glycosylphosphatidylinositols; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000378:metabolism*; D007249:Inflammation; D020935:MAP Kinase Signaling System; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*
D000951:Antigens, Neoplasm; D017261:Glycosylphosphatidylinositols; D017382:Reactive Oxygen Species; D006820:Hyaluronic Acid; D051548:Histone Acetyltransferases; C115866:OGA protein, human; D006821:Hyaluronoglucosaminidase