Institute of Experimental and Clinical Pharmacology and Toxicology, PZMS, ZHMB, Saarland University, 66421 Homburg, Germany.
Cells. 2022 Jul 26;11(15):2303. doi: 10.3390/cells11152303.
Severe epithelial dysfunction is one major hallmark throughout the pathophysiological progress of bacterial pneumonia. Junctional and cellular adhesion molecules (e.g., JAMA-A, ICAM-1), cytokines (e.g., TNFα), and growth factors (e.g., TGFα), controlling proper lung barrier function and leukocyte recruitment, are proteolytically cleaved and released into the extracellular space through a disintegrin and metalloproteinase (ADAM) 17. In cell-based assays, we could show that the protein expression, maturation, and activation of ADAM17 is upregulated upon infection of lung epithelial cells with and Exotoxin A (ExoA), without any impact of infection by . The characterization of released extracellular vesicles/exosomes and the comparison to heat-inactivated bacteria revealed that this increase occurred in a cell-associated and toxin-dependent manner. Pharmacological targeting and gene silencing of ADAM17 showed that its activation during infection with was critical for the cleavage of junctional adhesion molecule A (JAM-A) and epithelial cell survival, both modulating barrier integrity, epithelial regeneration, leukocyte adhesion and transepithelial migration. Thus, site-specific targeting of ADAM17 or blockage of the activating toxins may constitute a novel anti-infective therapeutic option in lung infection preventing severe epithelial and organ dysfunctions and stimulating future translational studies.
严重的上皮功能障碍是细菌性肺炎病理生理进展过程中的一个主要特征。连接蛋白和细胞黏附分子（例如 JAMA-A、ICAM-1）、细胞因子（例如 TNFα）和生长因子（例如 TGFα）控制着肺屏障功能和白细胞募集，它们通过解整合素金属蛋白酶（ADAM）17 被蛋白水解切割并释放到细胞外空间。在基于细胞的检测中，我们可以表明，肺上皮细胞感染 和肠毒素 A（ExoA）后，ADAM17 的蛋白表达、成熟和激活被上调，而 感染没有任何影响。对释放的细胞外囊泡/外泌体的特征描述以及与热灭活细菌的比较表明，这种增加是以细胞相关和毒素依赖的方式发生的。ADAM17 的药理学靶向和基因沉默表明，其在 感染期间的激活对于连接黏附分子 A（JAM-A）的切割和上皮细胞的存活至关重要，这两者都调节着屏障完整性、上皮再生、白细胞黏附和跨上皮迁移。因此，ADAM17 的特异性靶向或激活毒素的阻断可能构成一种新的抗感染治疗选择，可预防严重的上皮和器官功能障碍，并刺激未来的转化研究。
