The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia
The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia
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DOI：
10.1101/2022.09.03.506451
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发表时间：
2022-09
期刊：
影响因子：
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通讯作者：
Jeremy A. Herrera;Lewis A. Dingle;M. Montero;R. Venkateswaran;J. Blaikley;F. Granato;S. Pearson;C. Lawless;D. Thornton
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文献类型：
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作者：
Jeremy A. Herrera;Lewis A. Dingle;M. Montero;R. Venkateswaran;J. Blaikley;F. Granato;S. Pearson;C. Lawless;D. Thornton
蜂窝样变（HC）是一种组织学类型，与肺间质性肺炎（UIP）一致。HC是指位于具有显著粘液积聚的致密纤维化部位的囊性气道（HC气道）。利用激光捕获显微切割耦合质谱（LCM-MS），我们询问了10个UIP标本中的纤维化HC气道细胞和纤维化未受累气道细胞（远离UIP部位且形态完整）; 6个非纤维化气道细胞标本作为对照。此外，我们对6例UIP和6例粘液腺癌（MA）标本中发现的粘液栓进行了LCM-MS。对质谱数据进行定性和定量分析，并通过免疫组织化学进行验证。令人惊讶的是，纤维化未受累气道细胞与HC气道细胞共享相似的蛋白质谱，显示SLIT和ROBO途径的失调是最强的类别。我们发现BPIFB 1是UIP中最显著增加的分泌体相关蛋白，而MUC 5AC是MA中最显著增加的。我们的结论是，空间蛋白质组学表明，纤维化未参与气道细胞是异常的。此外，纤维化HC气道细胞富含粘蛋白生物发生蛋白，纤毛发生所必需的蛋白质明显紊乱。这种无偏倚的空间蛋白质组学方法将产生新的和可检验的假说来解释纤维化进展。
Honeycombing (HC) is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). HC refers to cystic airways (HC airways) located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic HC airway cells and fibrotic uninvolved airway cells (distant from sites of UIP and morphologically intact) in 10 UIP specimens; 6 non-fibrotic airway cell specimens served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 UIP and 6 mucinous adenocarcinoma (MA) specimens. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to HC airway cells, showing deregulation of SLITs and ROBO pathway as the strongest category. We find that BPIFB1 is the most significantly increased secretome-associated protein in UIP, whereas MUC5AC is the most significantly increased in MA. We conclude that spatial proteomics demonstrates that the fibrotic uninvolved airway cells are abnormal. In addition, fibrotic HC airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach will generate novel and testable hypotheses to decipher fibrosis progression.