Hypoxia-Inducible Factor-1α Regulates CD55 in Airway Epithelium

Abstract

Airway epithelial CD55 down-regulation occurs in several hypoxia-associated pulmonary diseases, but the mechanism is unknown. Using in vivo and in vitro assays of pharmacologic inhibition and gene silencing, the current study investigated the role of hypoxia-inducible factor (HIF)-1α in regulating airway epithelial CD55 expression. Hypoxia down-regulated CD55 expression on small-airway epithelial cells in vitro, and in murine lungs in vivo; the latter was associated with local complement activation. Treatment with pharmacologic inhibition or silencing of HIF-1α during hypoxia-recovered CD55 expression in small-airway epithelial cells. HIF-1α overexpression or blockade, in vitro or in vivo, down-regulated CD55 expression. Collectively, these data show a key role for HIF-1α in regulating the expression of CD55 on airway epithelium.

Hypoxia-induced complement dysregulation is associated with microvascular impairments in mouse tracheal transplants

“…While these studies have been important in showing how CRPs can be upregulated in cultured cells in hypoxic conditions, they cannot replicate the complex in vivo milieu of a rejecting transplant [47]. Inverse correlation of tissue expression of active complement components and CRPs have been crucial to the progress of transplant injury and associated tissue remodeling during rejection [48][49][50]. The key hypothesis to be tested in this manuscript is that during alloimmune inflammation, graft microvasculature and the airway epithelium is rendered susceptible to complement-mediated injury through decreased expression of major complement regulatory protein CD55 during a mouse model of OTT.…”

“…It has been well reported that HIF-1α, as the master regulator of oxygen homeostasis, is an important modulator of the tissue repair phase through its signaling in cell migration, cell survival, cell division, growth factor release, and matrix synthesis during the repair [56,57]. In addition, hypoxia results in tissue ischemia and the expression of a pro-inflammatory state through the downregulation of complement regulatory protein, CD55 [50]. The crucial role of pathological remodeling during persistent inflammation in small airways has been reported in both preclinical and clinical transplantation data, which obstruct the regeneration of airway epithelium and promote fibro-proliferation due to aberrant tissue repair [58][59][60][61][62].…”

Regulatory mechanisms of neutrophil migration from the circulation to the airspace

“… + ND Cell line, primary cell [ 25 , 152 , 292 , 320 , 330 , 331 ] ? + Apical Cell line, intestinal loop [ 190 , 292 ] CD55 + + ND Cell-free system, cell line [ 294 – 296 , 332 ] + + Apical Cell-free system, cell line [ 193 , 294 – 296 , 333 ] CD172α (SIRPα) ? a ND [ 25 ] + a Lateral Cell line [ 161 ] JAM-A (CD321) ?…”

Consecutive Hypoxia Decreases Expression of NOTCH3, HEY1, CC10, and FOXJ1 via NKX2-1 Downregulation and Intermittent Hypoxia-Reoxygenation Increases Expression of BMP4, NOTCH1, MKI67, OCT4, and MUC5AC via HIF1A Upregulation in Human Bronchial Epithelial Cells

“…In addition to H/R, consecutive hypoxia for a long period has also been reported to modulate the inflammatory functions and oxidant-induced cell injury in airway epithelial cells (Olson et al, 2011;Pahlman et al, 2015;Pandya et al, 2016;Polke et al, 2017). It was shown that consecutive hypoxia for longer than 24 h contributed to the pathogenesis of chronic pulmonary diseases via both the HIF1α-dependent downregulation of the complement regulatory protein CD55 and several inflammatory cytokines, including IL-6, IP-6, IP-10, and hBD-2, as well as the TGFβ1-dependent downregulation of the secretory leukocyte protease inhibitor, in human airway epithelial cells (Pahlman et al, 2015;Pandya et al, 2016;Polke et al, 2017).…”

“…In addition to H/R, consecutive hypoxia for a long period has also been reported to modulate the inflammatory functions and oxidant-induced cell injury in airway epithelial cells ( Olson et al, 2011 ; Pahlman et al, 2015 ; Pandya et al, 2016 ; Polke et al, 2017 ). It was shown that consecutive hypoxia for longer than 24 h contributed to the pathogenesis of chronic pulmonary diseases via both the HIF1α-dependent downregulation of the complement regulatory protein CD55 and several inflammatory cytokines, including IL-6, IP-6, IP-10, and hBD-2, as well as the TGFβ1-dependent downregulation of the secretory leukocyte protease inhibitor, in human airway epithelial cells ( Pahlman et al, 2015 ; Pandya et al, 2016 ; Polke et al, 2017 ). Continuous exposure to hypoxia for 24 h was also reported to inhibit active sodium absorption and the HIF2α- and NF-κB-dependent bacterial infection ( Tomlinson et al, 1999 ; Schaible et al, 2013 ), while hypoxia for 12 h was shown to increase HIF1α-dependent miR-200b expression and decrease expression of the cystic fibrosis transmembrane conductance regulator (CFTR) ( Bartoszewska et al, 2017 ), and hypoxia for 6 h was sufficient to significantly ameliorate the oxidant-induced epithelial barrier dysfunction ( Olson et al, 2011 ).…”