Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia.
Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia.
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人类原发性纤毛运动障碍中的抗原停滞和气道亚硝化应激。
DOI：
10.1152/ajplung.00208.2022
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Marozkina,Nadzeya
中科院分区：
文献类型：
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作者：
Gaston,Benjamin;Smith,LauraA;Davis,MichaelD;Saunders,Jessica;Daniels,Ivana;Horani,Amjad;Brody,StevenL;Giddings,Olivia;Zhao,Yi;Marozkina,Nadzeya
大多数原发性睫状体运动障碍(PCD)患者鼻腔一氧化氮(NNO)水平较低。纤毛运动减少可能导致抗原停滞，增加氧化剂的产生和呼吸道中的NO氧化。这既能降低气相NO含量，又能增加亚硝化应力。我们研究了来自健康对照(HCS)和几种不同基因型别的PCD患者的原代呼吸道上皮细胞。我们测量了顶端暴露于荧光标记的抗屋尘病抗原(DerP1-f)的开窗膜中的抗原清除率。我们对3-硝基酪氨酸(3-NT)和氧化反应酶进行了免疫印迹。我们测量了没有和有PCD致病基因的初级呼吸道细胞上方的顶空NO。在体内测定NNO和呼出的呼吸冷凝液(EBC)H_2O_2。从HC细胞中清除顶端DerP1-f的效果好于从PCD细胞中清除。DUOX1在染毒前和染毒24小时后，HC细胞的DUOX1表达均低于PCD细胞。HC细胞的3-NT和NO_3−均低于PCD细胞。然而，HC细胞消耗的NO少于PCD细胞；超氧化物歧化酶(SOD)和apocynin不能阻止NO的丢失。HCS患者血清NNO水平高于PCD患者。HC组EBC H_2O_2低于PCD组。PCD呼吸道上皮不能以最佳方式清除抗原，并受到氧化和亚硝化应激的影响。与抗原停滞相关的氧化可能是PCD的一个治疗靶点，具有方便的监测生物标志物。新与注PCD呼吸道上皮不能以最佳方式清除抗原，抗原暴露可导致NO氧化和亚硝化应激。抗原滞留引起的氧化反应可能是PCD的治疗靶点，并且有方便的监测生物标志物。
Nasal nitric oxide (nNO) is low in most patients with primary ciliary dyskinesia (PCD). Decreased ciliary motion could lead to antigen stasis, increasing oxidant production and NO oxidation in the airways. This could both decrease gas phase NO and increase nitrosative stress. We studied primary airway epithelial cells from healthy controls (HCs) and patients with PCD with several different genotypes. We measured antigen clearance in fenestrated membranes exposed apically to the fluorescently labeled antigenDermatophagoides pteronyssinus(Derp1-f). We immunoblotted for 3-nitrotyrosine (3-NT) and for oxidative response enzymes. We measured headspace NO above primary airway cells without and with a PCD-causing genotype. We measured nNO and exhaled breath condensate (EBC) H2O2in vivo. Apical Derp1-f was cleared from HC better than from PCD cells. DUOX1 expression was lower in HC than in PCD cells at baseline and after 24-h Derp1-f exposure. HC cells had less 3-NT and NO3−than PCD cells. However, NO consumption by HC cells was less than that by PCD cells; NO loss was prevented by superoxide dismutase (SOD) and by apocynin. nNO was higher in HCs than in patients with PCD. EBC H2O2was lower in HC than in patients with PCD. The PCD airway epithelium does not optimally clear antigens and is subject to oxidative and nitrosative stress. Oxidation associated with antigen stasis could represent a therapeutic target in PCD, one with convenient monitoring biomarkers.NEW & NOTEWORTHYThe PCD airway epithelium does not optimally clear antigens, and antigen exposure can lead to NO oxidation and nitrosative stress. Oxidation caused by antigen stasis could represent a therapeutic target in PCD, and there are convenient monitoring biomarkers.