中文摘要：

耐碳青霉烯肺炎克雷伯菌（CRKP）可引發革蘭氏陰性菌肺部感染及致死性肺炎膿毒癥，目前臨床可用治療手段十分有限。肺組織密集分布著傷害感受器感覺神經元，這類神經元負責調控呼吸、咳嗽與支氣管收縮功能。但傷害感受器在機體抵御革蘭氏陰性肺部病原菌感染中的作用尚不明確。

本研究發現，肺支配型傷害感受器會促進耐碳青霉烯肺炎克雷伯菌所致肺炎及肺炎膿毒癥的發生。在小鼠體內消融傷害感受器后，肺部對耐碳青霉烯肺炎克雷伯菌的清除能力顯著增強，病菌跨肺泡擴散受到抑制，同時可有效避免小鼠出現低體溫及死亡結局。

此外，消融傷害感受器能夠促進中性粒細胞和 Ly6C?單核細胞募集，并上調細胞因子表達。在神經元消融小鼠模型中，耗竭 Ly6C?單核細胞會消除肺部及肺外組織對耐碳青霉烯肺炎克雷伯菌的清除效應，而耗竭中性粒細胞則無此作用，提示Ly6C?單核細胞是調控肺炎膿毒癥的關鍵細胞群體。

進一步機制研究表明，神經肽降鈣素基因相關肽可抑制 Ly6C?單核細胞中活性氧的生成，并削弱其對耐碳青霉烯肺炎克雷伯菌的殺菌能力。綜上，靶向傷害感受器信號通路，有望成為治療多重耐藥革蘭氏陰性菌感染及肺炎膿毒癥的全新干預策略。

英文摘要：

Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6Chi monocytes and cytokine induction. Depletion of Ly6Chi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6Chi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene–related peptide suppressed the induction of reactive oxygen species in Ly6Chi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.

論文信息：

論文題目：Lung-innervating nociceptor sensory neurons promote pneumonic sepsis during carbapenem-resistant Klebsiella pneumoniae lung infection

期刊名稱：Science Advances

時間期卷：Vol 10, Issue 36(2024)

在線時間：2024年9月6日

DOI: 10.1126/sciadv.adl2267

產品信息：

貨號：CP-005-005

規格：5ml+5ml

品牌：Liposoma

產地：荷蘭

名稱：Clodronate Liposomes&Control Liposomes

辦事處：靶點科技

Clodronate Liposomes氯膦酸鹽脂質體在細菌感染模型種清除肺臟肺泡巨噬細胞。荷蘭Liposoma巨噬細胞清除劑ClodronateLiposomes見刊于Science Advances：肺傷害感受器感覺神經支配神經元，在耐碳青霉烯肺炎克雷伯菌肺部感染中促進肺炎性膿毒癥發生。

Liposoma巨噬細胞清除劑Clodronate Liposomes氯膦酸二鈉脂質體清除巨噬細胞的材料和方法：

Depletion of AMs

Mice were first anesthetized with a 100 mg ketamine/kg body weight (Ketaset) and 10 mg xylazine/kg body weight (Rompun) cocktail, followed by intratracheal administration of single dose of 70 μl of CLLs (Liposoma) at 48 hours before infection. Control mice were administered with PBLs (70 μl per mouse) (Liposoma).

巨噬細胞清除材料和方法文獻截圖：