Recruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis.
Recruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis.
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DOI：
10.1038/s12276-022-00770-8
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发表时间：
2022-05
影响因子：
12.8
通讯作者：
Bruscia, Emanuela M.
中科院分区：
文献类型：
--
作者：
Di Pietro, Caterina;Oz, Hasan H.;Zhang, Ping-xia;Cheng, Ee-chun;Martis, Valentino;Bonfield, Tracey L.;Kelley, Thomas J.;Jubin, Ronald;Abuchowski, Abraham;Krause, Diane S.;Egan, Marie E.;Murray, Thomas S.;Bruscia, Emanuela M.
压倒性的嗜酸性炎症是许多肺部疾病（包括囊性纤维化（CF））中肺损伤的主要原因。血红素加氧酶-1（HO-1）/一氧化碳（CO）通路介导炎症的消退，并且在CF影响的巨噬细胞（MΦ）中存在缺陷。在这里，我们提供的证据表明，PP-007，一个CO释放/O2转移剂，全身给药诱导HO-1的表达，髓样分化因子88（MyD 88）和磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（AKT）依赖的方式。它还挽救了响应于脂多糖（LPS）或铜绿假单胞菌（PA）诱导的CF影响的细胞中降低的HO-1水平。用单次临床相关剂量的PP-007治疗CF和粘膜阻塞性肺病小鼠模型导致肺嗜中性粒细胞症的有效消退和响应于LPS的促炎细胞因子水平的降低。使用HO-1条件性敲除小鼠，我们表明PP-007的有益作用是由于响应于感染而引发循环单核细胞运输到肺部以表达高水平的HO-1。最后，我们表明，PP-007不会损害PA在慢性气道感染的情况下的清除。总体而言，我们揭示了PP-007的作用机制，该机制负责在广泛疾病的临床试验中观察到的免疫调节功能，并证明了PP-007通过促进单核细胞/巨噬细胞中HO-1的表达来控制嗜酸性肺部炎症的潜在用途。一种在囊性纤维化（CF）中显著降低的酶的活性可以通过现有的药物来增强，从而减少肺部炎症和相关的组织损伤。CF中的慢性炎症目前使用长期皮质类固醇治疗，这可能会使患者免疫抑制，或使用耐受性不佳的高剂量布洛芬。科学家们希望找到针对慢性炎症的替代疗法。Emanuela Emanuela，Caterina Di Pietro（美国纽黑文耶鲁大学）及其同事研究了一流药物PP-007（Prolong Pharmaceuticals®）的作用机制，并评估了其控制CF炎症的潜力。患有CF的患者在称为单核细胞的免疫细胞中血红素加氧酶-1的表达减少。在CF小鼠模型中，用PP-007处理增强了这种酶在循环单核细胞中的表达。治疗降低了促炎蛋白的水平和相关的肺损伤。
Overwhelming neutrophilic inflammation is a leading cause of lung damage in many pulmonary diseases, including cystic fibrosis (CF). The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway mediates the resolution of inflammation and is defective in CF-affected macrophages (MΦs). Here, we provide evidence that systemic administration of PP-007, a CO releasing/O2 transfer agent, induces the expression of HO-1 in a myeloid differentiation factor 88 (MyD88) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-dependent manner. It also rescues the reduced HO-1 levels in CF-affected cells induced in response to lipopolysaccharides (LPS) or Pseudomonas aeruginosa (PA). Treatment of CF and muco-obstructive lung disease mouse models with a single clinically relevant dose of PP-007 leads to effective resolution of lung neutrophilia and to decreased levels of proinflammatory cytokines in response to LPS. Using HO-1 conditional knockout mice, we show that the beneficial effect of PP-007 is due to the priming of circulating monocytes trafficking to the lungs in response to infection to express high levels of HO-1. Finally, we show that PP-007 does not compromise the clearance of PA in the setting of chronic airway infection. Overall, we reveal the mechanism of action of PP-007 responsible for the immunomodulatory function observed in clinical trials for a wide range of diseases and demonstrate the potential use of PP-007 in controlling neutrophilic pulmonary inflammation by promoting the expression of HO-1 in monocytes/macrophages. The activity of an enzyme that is significantly reduced in cystic fibrosis (CF) could be boosted by an existing drug, reducing lung inflammation and associated tissue damage. Chronic inflammation in CF is currently treated using long-term corticosteroids which may leave patients immuno-suppressed, or high-dose ibuprofen, which is not well tolerated. Scientists hope to find alternative therapies targeting chronic inflammation. Emanuela Bruscia, Caterina Di Pietro (Yale University, New Haven, USA) and co-workers examined the mechanisms of action of the first-in-class drug PP-007 (Prolong Pharmaceuticals®) and assessed its potential for controlling inflammation in CF. Patients with CF have reduced expression of the heme oxygenase-1 enzyme in immune cells called monocytes. In CF mouse models, treatment with PP-007 boosted the expression of this enzyme in circulating monocytes. The treatment reduced levels of proinflammatory proteins and associated lung damage.
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影响因子：
168.9
作者：
Heijerman, Harry G. M.;McKone, Edward F.;Mccoy, Karen S.
通讯作者：
Mccoy, Karen S.
影响因子：
2.1
作者：
Abu Jawdeh, Bassam G.;Woodle, Ervin Steve;Alloway, Rita R.
通讯作者：
Alloway, Rita R.
影响因子：
5.3
作者：
Bruscia EM;Bonfield TL
通讯作者：
Bonfield TL
影响因子：
4.6
作者：
Di Pietro C;Zhang PX;O'Rourke TK;Murray TS;Wang L;Britto CJ;Koff JL;Krause DS;Egan ME;Bruscia EM
通讯作者：
Bruscia EM
影响因子：
2.2
作者：
Mamiya, Takashi;Katsuoka, Fumiki;Hosoya, Tomonori
通讯作者：
Hosoya, Tomonori