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Leukocyte kinetics and bacterial clearance during Streptococcus pneumoniae pneumonia and contributions of ICAM-1. 肺炎双球菌肺炎期间的白细胞动力学和细菌清除以及 ICAM-1 的作用。
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-10-22 DOI: 10.1152/ajplung.00039.2024
Matthew K McPeek, John C Gomez, Jessica R Martin, Marie Anne Iannone, Hong Dang, Claire M Doerschuk

Streptococcus pneumoniae is a leading cause of community-acquired pneumonia. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that is highly expressed on the pulmonary capillary endothelium, alveolar epithelium, and other cell types within the lung. ICAM-1 plays important roles in leukocyte adhesion, migration, and motility. To determine the contributions of ICAM-1 to bacterial clearance and leukocyte kinetics during pneumonia, mice were inoculated with S. pneumoniae and evaluated 1, 4, and 7 days later. Our results show that Icam1-/- mice have a greater number of viable bacteria within the lung at each time point. The impaired clearance observed in Icam1-/- mice was not due to an impediment in leukocyte recruitment. In fact, Icam1-/- mice had a greater number of neutrophils and recruited inflammatory macrophages in the lung tissue and the alveoli/airways on day 7. In contrast, fewer alveolar macrophages were present in the bronchoalveolar lavage (BAL) of Icam1-/- mice. The loss of body weight and the concentrations of inflammatory mediators in the BAL were also significantly greater in Icam1-/- mice. Mechanistic studies to understand the defect in clearance show that neutrophils and macrophage subpopulations had no defect in phagocytosis or acidification of phagosomes. RNA sequencing reveals many differences in gene expression but no suggestion of a defect in phagocytosis or killing. Thus, ICAM-1 is necessary for the clearance of S. pneumoniae and for the resolution of pneumonia but is not required for the recruitment of neutrophils or inflammatory macrophages into the pneumonic lung parenchyma or the alveoli/airways during S. pneumoniae-induced pneumonia.NEW & NOTEWORTHY Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. Our study examined ICAM-1, an adhesion molecule that is expressed on most cell types and plays important roles in leukocyte adhesion, migration, and motility. The data demonstrate that ICAM-1 is necessary for the clearance of S. pneumoniae and for the resolution of pneumonia but is not required for the recruitment of neutrophils or inflammatory macrophages into the pneumonic lung parenchyma or the alveoli/airways.

肺炎链球菌是社区获得性肺炎的主要病因。细胞间粘附分子-1(ICAM-1)是一种粘附分子,在肺毛细血管内皮、肺泡上皮和肺部其他类型的细胞上高度表达。ICAM-1 在白细胞粘附、迁移和运动中发挥着重要作用。为了确定 ICAM-1 在肺炎期间对细菌清除和白细胞动力学的贡献,我们给小鼠接种了肺炎双球菌,并在 1、4 和 7 天后进行了评估。我们的结果表明,在每个时间点,Icam1-/小鼠肺内的存活细菌数量都更多。在 Icam1-/- 小鼠身上观察到的清除能力减弱并不是因为白细胞招募受阻。事实上,在第 7 天,Icam1-/- 小鼠的肺组织和肺泡/气道中有更多的中性粒细胞和招募的炎性巨噬细胞。相反,Icam1-/-小鼠的BAL中肺泡巨噬细胞数量较少。Icam1-/-小鼠体重的减少和BAL中炎症介质的浓度也明显增加。为了解清除缺陷而进行的机制研究表明,中性粒细胞和巨噬细胞亚群在吞噬或吞噬体酸化方面没有缺陷。RNA 测序显示基因表达存在许多差异,但没有发现吞噬或杀伤缺陷。因此,ICAM-1 对于肺炎双球菌的清除和肺炎的消退是必需的,但在肺炎双球菌诱发肺炎期间,中性粒细胞或炎症巨噬细胞被招募到肺炎肺实质或肺泡/气道中则不是必需的。
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引用次数: 0
Navigating the extravascular lung waters of pulmonary edema in COVID-19 ARDS. COVID-19 ARDS患者肺水肿血管外肺水的导航
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-12-11 DOI: 10.1152/ajplung.00383.2024
Pranav Jain, Georgios D Kitsios
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引用次数: 0
Dynamic driving pressure predicts ventilator-induced lung injury in mice with and without endotoxin-induced acute lung injury. 动态驱动压力可预测有内毒素诱发和无内毒素诱发急性肺损伤的小鼠呼吸机诱发的肺损伤。
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-11-27 DOI: 10.1152/ajplung.00176.2024
Alison Wallbank, Alexander Sosa, Andrew Colson, Huda Farooqi, Elizabeth Kaye, Katharine Warner, David J Albers, Peter D Sottile, Bradford J Smith

Mechanical ventilation (MV) is a necessary lifesaving intervention for patients with acute respiratory distress syndrome (ARDS) but it can cause ventilator-induced lung injury (VILI), which contributes to the high ARDS mortality rate (∼40%). Bedside determination of optimally lung-protective ventilation settings is challenging because the evolution of VILI is not immediately reflected in clinically available, patient-level, data. The goal of this work was therefore to test ventilation waveform-derived parameters that represent the degree of ongoing VILI and can serve as targets for ventilator adjustments. VILI was generated at three different positive end-expiratory pressures in a murine inflammation-mediated (lipopolysaccharide, LPS) acute lung injury model and in initially healthy controls. LPS injury increased the expression of proinflammatory cytokines and caused widespread atelectasis, predisposing the lungs to VILI as measured in structure, mechanical function, and inflammation. Changes in lung function were used as response variables in an elastic net regression model that predicted VILI severity from tidal volume, dynamic driving pressure (PDDyn), mechanical power calculated by integration during inspiration or the entire respiratory cycle, and power calculated according to Gattinoni' s equation. Of these, PDDyn best predicted functional outcomes of injury using either data from the entire dataset or from 5-min time windows. The windowed data show higher predictive accuracy after an ∼1-h "run in" period and worse accuracy immediately following recruitment maneuvers. This analysis shows that low driving pressure is a computational biomarker associated with better experimental VILI outcomes and supports the use of driving pressure to guide ventilator adjustments to prevent VILI.NEW & NOTEWORTHY Elastic net regression analysis of ventilation waveforms recorded during mechanical ventilation of initially healthy and lung-injured mice shows that low driving pressure is a computational biomarker associated with better ventilator-induced lung injury (VILI) outcomes and supports the use of driving pressure to guide ventilator adjustments to prevent VILI.

机械通气是拯救急性呼吸窘迫综合征(ARDS)患者生命的必要干预措施,但它可能导致呼吸机诱发肺损伤(VILI),从而导致 ARDS 死亡率居高不下(≈40%)。床旁确定最佳肺保护通气设置具有挑战性,因为 VILI 的演变并不能立即反映在临床可用的患者层面数据中。因此,这项工作的目标是测试通气波形衍生参数,这些参数可代表正在发生的 VILI 的程度,并可作为呼吸机调整的目标。在小鼠炎症介导的(脂多糖,LPS)急性肺损伤模型和初始健康对照组中,在三种不同的呼气末正压下产生了 VILI。LPS 损伤增加了促炎细胞因子的表达,并导致广泛的肺不张,从而使肺部结构、机械功能和炎症更易发生 VILI。肺功能的变化被用作弹性网回归模型中的响应变量,该模型通过潮气量、动态驱动压力(PDDyn)、吸气或整个呼吸周期中整合计算的机械功率以及根据加蒂诺尼方程计算的功率来预测 VILI 的严重程度。其中,PDDyn 使用整个数据集或 5 分钟时间窗的数据对损伤功能结果的预测效果最佳。窗口数据显示,经过≈1 小时的 "磨合期 "后,预测准确性更高,而在招募动作后立即进行预测的准确性则更低。该分析表明,低驱动压力是一种计算生物标志物,与较好的 VILI 实验结果相关,并支持使用驱动压力来指导呼吸机调整以预防 VILI。
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引用次数: 0
Pulmonary-delivered Anticalin Jagged-1 antagonists reduce experimental airway mucus hyperproduction and obstruction. 肺部给药的安替卡林 Jagged-1 拮抗剂可减少实验性气道粘液过度分泌和阻塞。
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-11-05 DOI: 10.1152/ajplung.00059.2024
Katharina Heinzelmann, Athanasios Fysikopoulos, Thomas J Jaquin, Janet K Peper-Gabriel, Eva-Maria Hansbauer, Stefan Grüner, Josef Prassler, Claudia Wurzenberger, Joseph G C Kennedy, Jazmin Y Snead, Joe A Wrennall, Kristina Heinig, Cornelia Wurzenberger, Rachida-Siham Bel Aiba, Robert Tarran, Alessandra Livraghi-Butrico, Mary F Fitzgerald, Gary P Anderson, Christine Rothe, Gabriele Matschiner, Shane A Olwill, Matthias Hagner

Mucus hypersecretion and mucus obstruction are pathogenic features in many chronic lung diseases directly linked to disease severity, exacerbation, progression, and mortality. The Jagged-1/Notch pathway is a promising therapeutic target that regulates secretory and ciliated cell trans-differentiation in the lung. However, the Notch pathway is also required in various other organs. Hence, pulmonary delivery of therapeutic agents is a promising approach to target this pathway while minimizing systemic exposure. Using Anticalin technology, Jagged-1 Anticalin binding proteins were generated and engineered to potent and selective inhalable Jagged-1 antagonists. Their therapeutic potential to reduce airway mucus hyperproduction and obstruction was investigated ex vivo and in vivo. In primary airway cell cultures grown at an air-liquid interface and stimulated with inflammatory cytokines, Jagged-1 Anticalin binding proteins reduced both mucin gene expression and mucous cell metaplasia. In vivo, prophylactic and therapeutic treatment with a pulmonary-delivered Jagged-1 Anticalin binding protein reduced mucous cell metaplasia, epithelial thickening, and airway mucus hyperproduction in IL-13 and house dust mite allergen-challenged mice, respectively. Furthermore, in a transgenic mouse model with pathophysiologic features of cystic fibrosis and chronic obstructive pulmonary disease (COPD), pulmonary-delivered Jagged-1 Anticalin binding protein reduced hallmarks of airway mucus obstruction. In all in vivo models, a reduction of mucous cells with a concomitant increase of ciliated cells was observed. Collectively, these findings support Jagged-1 antagonists' therapeutic potential for patients with muco-obstructive lung diseases and the feasibility of targeting the Jagged-1/Notch pathway by inhalation.NEW & NOTEWORTHY Airway mucus drives severity and mortality in diverse chronic lung diseases. The Jagged-1/Notch pathway controls the balance of ciliated versus mucous cells, but targeting the pathway systemically carries the risk of side effects. Here we developed novel, Anticalin-derived, pulmonary-delivered Jagged-1 antagonists, to inhibit airway mucus hyperproduction and obstruction in chronic lung diseases. Our preclinical data demonstrate the effectiveness of these antagonists in diminishing secretory cell and mucus levels and alleviating hallmarks of mucus obstruction.

粘液分泌过多和粘液阻塞是许多慢性肺病的致病特征,与疾病的严重程度、恶化、进展和死亡率直接相关。Jagged-1/Notch通路是一个很有前景的治疗靶点,它能调节肺部分泌细胞和纤毛细胞的转分化。然而,其他器官也需要 Notch 通路。因此,肺部给药是一种很有前景的方法,既能靶向这一途径,又能最大限度地减少全身暴露。利用 Anticalin® 技术生成了 Jagged-1 Anticalin 结合蛋白,并将其设计为强效、选择性的可吸入 Jagged-1 拮抗剂。研究人员对这些拮抗剂减少气道粘液过度分泌和阻塞的治疗潜力进行了体内外研究。在气-液界面生长的原发性气道细胞培养物中,在炎症细胞因子的刺激下,Jagged-1 Anticalin 结合蛋白可减少粘蛋白基因的表达和粘液细胞的增生。在体内,使用肺部投放的 Jagged-1 Anticalin 结合蛋白进行预防性和治疗性治疗,可分别减少 IL-13 和屋尘螨过敏原致敏小鼠的粘液细胞增生、上皮增厚和气道粘液亢进。此外,在具有囊性纤维化和慢性阻塞性肺病病理生理特征的转基因小鼠模型中,肺输送的 Jagged-1 抗原结合蛋白减少了气道粘液阻塞的特征。在所有体内模型中,都观察到粘液细胞减少,同时纤毛细胞增加。总之,这些研究结果支持 Jagged-1 拮抗剂对粘液阻塞性肺病患者的治疗潜力,以及通过吸入靶向 Jagged-1/Notch 通路的可行性。
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引用次数: 0
Antenatal steroids enhance long-term neonatal lung outcomes and are associated with placental alterations in experimental chorioamnionitis. 产前类固醇增强新生儿长期肺预后,并与实验性绒毛膜羊膜炎胎盘改变有关。
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-12-19 DOI: 10.1152/ajplung.00204.2024
Adom Netsanet, Gregory J Seedorf, Steven H Abman, Elizabeth S Taglauer

Intrauterine inflammation from chorioamnionitis (CA) is associated with placental dysfunction and increased risk of bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity. Antenatal steroid (ANS) treatment improves early respiratory outcomes for premature infants. However, it remains unclear whether ANS improves long-term respiratory outcomes, and whether these effects are mediated through the improvement of placental dysfunction and/or direct impact on the fetal lung. We hypothesized that maternal ANS therapy preserves long-term lung development and impacts placental structural changes and gene expression in experimental CA with features of BPD. Pregnant rat dams were administered either saline (CTL), intra-amniotic (IA) endotoxin (ETX), ETX plus intramuscular (IM) betamethasone (ETX + BETA), or IM BM alone (BETA) on embryonic day 20 (E20). We collected placental tissue at delivery (E22) and infant lung tissue on the day of life (DOL) 14. In comparison with controls, IA ETX had impaired infant lung growth and function. Maternal BM treatment of ETX-exposed pregnant dams reduced infant total lung resistance by 15.3% (P < 0.05), improved infant lung compliance by 9.5% (P < 0.05), preserved alveolar and vascular growth (P < 0.05), and improved right ventricular hypertrophy (RVH) by 42.4% (P < 0.05). ETX + BETA pregnancies were also associated with normalization of placental spiral artery modification and altered placental gene expression. These included the upregulation of placental prolactin, which has regulatory effects on pregnancy homeostasis and has been clinically associated with decreased BPD risk. The current study identifies parallel lung and placental changes associated with ANS treatment, providing a foundation for future studies to identify alternate antenatal therapies with more specific efficacy for BPD prevention.NEW & NOTEWORTHY We performed parallel neonatal lung and placental analyses in a preclinical model to characterize the impact of antenatal betamethasone in experimental chorioamnionitis. Antenatal steroids improved long-term respiratory outcomes and were associated with concurrent structural and molecular changes in the placenta. This study establishes an important model system for future analyses to evaluate mechanistic links determining whether the long-term impact of antenatal steroids on lung development may be through alteration of placental function.

绒毛膜羊膜炎(CA)引起的宫内炎症与胎盘功能障碍和支气管肺发育不良(BPD)的风险增加有关,BPD是早产儿的慢性肺部疾病。产前类固醇(ANS)治疗可改善早产儿早期呼吸结局。然而,尚不清楚ANS是否能改善长期呼吸预后,以及这些影响是否通过改善胎盘功能障碍和/或直接影响胎儿肺来介导。我们假设母体ANS治疗保留了具有BPD特征的实验性CA的长期肺发育,并影响了胎盘结构变化和基因表达。孕鼠在胚胎第20天(e20)分别给予生理盐水(CTL)、羊膜内毒素(ETX)、ETX加肌内倍他米松(ETX+BETA)或单独注射IM BM (BETA)。我们收集了分娩时的胎盘组织(e22)和出生后第14天的婴儿肺组织(DOL)。与对照组相比,IA ETX损害了婴儿的肺生长和功能。母体对暴露于etx的孕鼠进行BM治疗,可使婴儿总肺阻力降低15.3% (p
{"title":"Antenatal steroids enhance long-term neonatal lung outcomes and are associated with placental alterations in experimental chorioamnionitis.","authors":"Adom Netsanet, Gregory J Seedorf, Steven H Abman, Elizabeth S Taglauer","doi":"10.1152/ajplung.00204.2024","DOIUrl":"10.1152/ajplung.00204.2024","url":null,"abstract":"<p><p>Intrauterine inflammation from chorioamnionitis (CA) is associated with placental dysfunction and increased risk of bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity. Antenatal steroid (ANS) treatment improves early respiratory outcomes for premature infants. However, it remains unclear whether ANS improves long-term respiratory outcomes, and whether these effects are mediated through the improvement of placental dysfunction and/or direct impact on the fetal lung. We hypothesized that maternal ANS therapy preserves long-term lung development and impacts placental structural changes and gene expression in experimental CA with features of BPD. Pregnant rat dams were administered either saline (CTL), intra-amniotic (IA) endotoxin (ETX), ETX plus intramuscular (IM) betamethasone (ETX + BETA), or IM BM alone (BETA) on <i>embryonic day 20</i> (E20). We collected placental tissue at delivery (E22) and infant lung tissue on the <i>day of life</i> (DOL) <i>14</i>. In comparison with controls, IA ETX had impaired infant lung growth and function. Maternal BM treatment of ETX-exposed pregnant dams reduced infant total lung resistance by 15.3% (<i>P</i> < 0.05), improved infant lung compliance by 9.5% (<i>P</i> < 0.05), preserved alveolar and vascular growth (<i>P</i> < 0.05), and improved right ventricular hypertrophy (RVH) by 42.4% (<i>P</i> < 0.05). ETX + BETA pregnancies were also associated with normalization of placental spiral artery modification and altered placental gene expression. These included the upregulation of placental prolactin, which has regulatory effects on pregnancy homeostasis and has been clinically associated with decreased BPD risk. The current study identifies parallel lung and placental changes associated with ANS treatment, providing a foundation for future studies to identify alternate antenatal therapies with more specific efficacy for BPD prevention.<b>NEW & NOTEWORTHY</b> We performed parallel neonatal lung and placental analyses in a preclinical model to characterize the impact of antenatal betamethasone in experimental chorioamnionitis. Antenatal steroids improved long-term respiratory outcomes and were associated with concurrent structural and molecular changes in the placenta. This study establishes an important model system for future analyses to evaluate mechanistic links determining whether the long-term impact of antenatal steroids on lung development may be through alteration of placental function.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L197-L205"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Citrullinated and malondialdehyde-acetaldehyde-modified fibrinogen activates macrophages and promotes profibrotic responses in human lung fibroblasts. 瓜氨酸化和丙二醛-乙醛修饰的纤维蛋白原能激活巨噬细胞并促进人肺成纤维细胞的损伤性反应。
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-11-19 DOI: 10.1152/ajplung.00153.2024
Nozima Aripova, Michael J Duryee, Wenxian Zhou, Bryant R England, Carlos D Hunter, Lauren E Klingemann, Nigina Aripova, Amy J Nelson, Dawn Katafiasz, Kristina L Bailey, Jill A Poole, Geoffrey M Thiele, Ted R Mikuls

The objective of this study was to assess fibrinogen (FIB) comodified with citrulline (CIT) and/or malondialdehyde-acetaldehyde (MAA) initiates macrophage-fibroblast interactions, leading to extracellular matrix (ECM) deposition that characterizes rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Macrophages (Mϕ) were stimulated with native-FIB, FIB-CIT, FIB-MAA, or FIB-MAA-CIT. Supernatants (SNs) [Mϕ-SN (U-937-derived) or MϕP-SN (PBMC-derived)] or direct antigens were coincubated with human lung fibroblasts (HLFs). Gene expression was examined using RT-PCR. ECM deposition was quantified using immunohistochemistry and Western blot; cell signaling mechanisms were delineated. Platelet-derived growth factor (PDGF)-BB and TGF-β were measured in macrophage supernatants, and inhibition studies were performed using Su16f and SB431542, respectively. HLF gene expression of CD36, COL6A3, MMP-9, MMP-10, and MMP-12 was increased following stimulations with Mϕ-SN generated from modified FIB but not from direct antigens. HLF stimulated with MϕP-SNFIB-MAA-CIT derived from patients with RA-ILD resulted in 4- to 30-fold increases in COL6A3 and MMP12 expression; upregulation was greater in HLFs stimulated with MϕP-SN derived from RA-ILD versus controls. HLF exposure to Mϕ-SNFIB-MAA-CIT increased types I/VI collagen deposition versus all other Mϕ-SN groups and was greater than FIB-MAA-CIT stimulation. PDGF-BB and TGF-β signaling had the highest concentrations identified in Mϕ-SNFIB-MAA-CIT and MϕP-SNFIB-MAA-CIT, particularly from RA-ILD-derived cells. PDGF-BB and TGF-β inhibitors, alone and in combination, significantly reduced HLF-mediated ECM deposition from Mϕ-SN stimulations. These results show that comodified fibrinogen activates macrophages to produce PDGF-BB and TGF-β that promotes an aggressive HLF phenotype characterized by increased ECM deposition. These results suggest that targeting CIT and/or MAA modifications or downstream cellular signals could represent novel approaches to RA-ILD treatment.NEW & NOTEWORTHY This report demonstrates that fibrinogen simultaneously harboring two common posttranslational modifications activates macrophages to secrete platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-β. Resulting cross talk between activated macrophages and human lung fibroblasts leads to marked increases in extracellular matrix deposition. These protein modifications are abundant and colocalize in lung tissues from patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), and the results suggest that agents targeting citrullination and/or malondialdehyde-acetaldehyde (MAA) adduct formation could represent novel therapeutic strategies.

本研究的目的是评估与瓜氨酸(CIT)和/或丙二醛-乙醛(MAA)共同修饰的纤维蛋白原(FIB)会引发巨噬细胞-成纤维细胞相互作用,导致细胞外基质(ECM)沉积,而细胞外基质沉积是类风湿性关节炎相关性间质性肺病(RA-ILD)的特征。用原生 FIB、FIB-CIT、FIB-MAA 或 FIB-MAA-CIT 刺激巨噬细胞(Mϕ)。将上清液(SN)(Mϕ-SN [U-937 衍生] 或 MϕP-SN [PBMC 衍生])或直接抗原与人肺成纤维细胞(HLFs)共培养。使用 RT-PCR 检测基因表达。使用免疫组化和 Western 印迹对 ECM 沉积进行量化;对细胞信号传导机制进行描述。在巨噬细胞上清液中测量了 PDGF-BB 和 TGF-,并分别使用 Su16f 和 SB431542 进行了抑制研究。用改良 FIB 产生的 Mϕ-SN 刺激 HLF 后,CD36、COL6A3、MMP-9、MMP-10 和 MMP-12 的基因表达增加,而直接抗原的表达则没有增加。用来自 RA-ILD 患者的 MϕP-SNFIB-MAA-CIT 刺激 HLF 会导致 COL6A3 和 MMP12 表达增加 4 到 30 倍;与对照组相比,用来自 RA-ILD 的 MϕP-SN 刺激 HLF 的上调幅度更大。与所有其他 Mϕ-SN 组相比,暴露于 Mϕ-SNFIB-MAA-CIT 的 HLF 增加了 I/VI 型胶原蛋白沉积,并且高于 FIB-MAA-CIT 刺激。PDGF-BB和TGF-信号在Mϕ-SNFIB-MAA-CIT和MϕP-SNFIB-MAA-CIT中浓度最高,尤其是来自RA-ILD衍生细胞的信号。PDGF-BB 和 TGF- 抑制剂单独或联合使用可显著减少 HLF 介导的来自 Mϕ-SN 刺激的 ECM 沉积。这些结果表明,共修饰的纤维蛋白原能激活巨噬细胞产生 PDGF-BB 和 TGF-β,从而促进以 ECM 沉积增加为特征的侵袭性 HLF 表型。这些结果表明,针对 CIT 和/或 MAA 修饰或下游细胞信号可能是治疗 RA-ILD 的新方法。
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引用次数: 0
Hypoxic effects of heroin and fentanyl and their basic physiological mechanisms. 海洛因和芬太尼的缺氧效应及其基本生理机制
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-15 DOI: 10.1152/ajplung.00251.2024
Eugene A Kiyatkin

Respiratory depression that diminishes oxygen delivery to the brain is the most dangerous effect of opioid drugs. Although plethysmography is a valuable tool to examine drug-induced changes in respiration, the primary cause of brain abnormalities induced by opioids is the global decrease in brain oxygen levels. The primary goal of this review is to provide an overview and discussion on fluctuations in brain oxygen levels induced by opioids, with a focus on heroin and fentanyl. To evaluate fluctuations in brain oxygen levels, we used oxygen sensors coupled with high-speed amperometry in awake, freely moving rats. First, we provide an overview of brain oxygen responses induced by natural physiological stimuli and discuss the mechanisms regulating oxygen entry into brain tissue. Then, we present data on brain oxygen responses induced by heroin and fentanyl and review their underlying mechanisms. These data allowed us to compare the effects of these drugs on brain oxygen regarding their latency, potency, time-dependency, and potential lethality at high doses as well as their relationships with peripheral oxygen responses. We also discuss data on the effects of naloxone on brain oxygen responses induced by heroin and fentanyl in the paradigms of both the pretreatment and treatment, when naloxone is administered at different times after the primary opioid drug. Although most data discussed were obtained in rats, they may have clinical relevance for understanding the mechanisms underlying the physiological effects of opioids and developing rational treatment strategies to decrease acute lethality and long-term health complications of opioid misuse.

呼吸抑制会减少向大脑输送氧气,这是阿片类药物最危险的影响。虽然胸透是检查药物引起的呼吸变化的重要工具,但阿片类药物引起脑部异常的主要原因是脑氧水平的全面下降。本综述的主要目的是概述和讨论阿片类药物引起的脑氧水平波动,重点是海洛因和芬太尼。为了评估脑氧水平的波动,我们在清醒、自由活动的大鼠身上使用了氧传感器和高速安培计。首先,我们概述了自然生理刺激引起的脑氧反应,并讨论了氧气进入脑组织的调节机制。然后,我们介绍了海洛因和芬太尼诱导的脑氧反应数据,并回顾了其基本机制。通过这些数据,我们可以比较这些药物在潜伏期、效力、时间依赖性、高剂量时的潜在致死性等方面对脑氧的影响,以及它们与外周氧反应的关系。我们还讨论了纳洛酮对海洛因和芬太尼诱导的脑氧反应的影响数据,包括预处理和治疗两种范例,即在主要阿片类药物之后的不同时间施用纳洛酮。虽然讨论的大多数数据都是在大鼠身上获得的,但这些数据可能具有临床意义,有助于了解阿片类药物生理效应的基本机制,并制定合理的治疗策略,以降低阿片类药物滥用的急性致死率和长期健康并发症。
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引用次数: 0
Disruption of immune responses by type 1 diabetes exacerbates SARS-CoV-2 mediated lung injury. I 型糖尿病对免疫反应的干扰加剧了 SARS-CoV-2 导致的肺损伤。
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-25 DOI: 10.1152/ajplung.00250.2024
Sara Kass-Gergi, Gan Zhao, Joanna Wong, Aaron I Weiner, Stephanie Adams Tzivelekidis, Maria E Gentile, Meryl Mendoza, Nicolas P Holcomb, Xinyuan Li, Madeline Singh, Yuru Huang, Alena Klochkova, Andrew E Vaughan

COVID-19 commonly presents as pneumonia, with those most severely affected progressing to respiratory failure. Patient responses to SARS-CoV-2 infection are varied, with comorbidities acting as major contributors to varied outcomes. Focusing on one such major comorbidity, we assessed whether pharmacological induction of type 1 diabetes mellitus (T1DM) would increase the severity of lung injury in a murine model of COVID-19 pneumonia utilizing wild-type mice infected with mouse-adapted SARS-CoV-2. Hyperglycemic mice exhibited increased weight loss and reduced blood oxygen saturation in comparison with their euglycemic counterparts, suggesting that these animals indeed experienced more severe lung injury. Transcriptomic analysis revealed a significant impairment of the adaptive immune response in the lungs of diabetic mice compared with those of control. To expand the limited options available for tissue analysis due to biosafety restrictions, we also employed a new technique to digest highly fixed tissue into a single-cell suspension, originally designed for scRNA-Seq, which we then adapted for flow cytometric analysis. Flow immunophenotyping and scRNA-Seq confirmed impaired recruitment of T-cells into the lungs of T1DM animals. In addition, scRNA-Seq revealed a distinct, highly inflammatory macrophage profile in the diabetic cohort that correlates with the more severe infection these mice experienced clinically, allowing insight into a possible mechanism for this phenomenon. Recognizing the near certainty that respiratory viruses will continue to present significant public health concerns for the foreseeable future, our study provides key insights into how T1DM results in a much more severe infection and identifies possible targets to ameliorate comorbidity-associated severe disease.NEW & NOTEWORTHY We define the exacerbating effects of type 1 diabetes mellitus (T1DM) on COVID-19 pneumonia severity in mice. Hyperglycemic mice experienced increased weight loss and reduced oxygen saturation. Transcriptomic analysis revealed impaired immune responses in diabetic mice, while flow cytometry and single-cell RNA sequencing confirmed reduced T-cell recruitment and an inflammatory macrophage profile. In addition, we introduced a novel technique for tissue analysis, enabling flow cytometric analysis on highly fixed tissue samples.

COVID-19 通常表现为肺炎,病情最严重者会发展为呼吸衰竭。患者对 SARS-CoV-2 感染的反应各不相同,合并症是导致不同结果的因素之一。针对其中一种主要的合并症,我们评估了在利用野生型小鼠感染小鼠适应型 SARS-CoV-2 的 COVID-19 肺炎模型中,药物诱导 I 型糖尿病 (T1DM) 是否会增加肺损伤的严重程度。与优血糖小鼠相比,高血糖小鼠表现出体重减轻和血氧饱和度降低,这表明这些动物确实经历了更严重的肺损伤。转录组分析显示,与对照组相比,糖尿病小鼠肺部的适应性免疫反应明显受损。由于生物安全性的限制,为了扩大组织分析的选择范围,我们采用了一种新技术,将高度固定的组织消化成单细胞悬液,这种技术最初是为 scRNA-Seq 设计的,后来我们将其用于流式细胞分析。流式免疫分型和 scRNA-Seq 证实,T1DM 动物肺部的 T 细胞招募功能受损。此外,scRNA-Seq 还揭示了糖尿病组群中巨噬细胞的独特、高度炎症性特征,这与这些小鼠在临床上经历的更严重感染有关,从而让我们了解了这一现象的可能机制。在可预见的未来,呼吸道病毒几乎肯定会继续引起重大的公共卫生问题,我们的研究为了解 T1DM 如何导致更严重的感染提供了重要见解,并确定了可能的靶点,以改善与并发症相关的严重疾病。
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引用次数: 0
Identification of FGFR4 as a regulator of myofibroblast differentiation in pulmonary fibrosis. 确定 FGFR4 是肺纤维化肌成纤维细胞分化的调节因子
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-01 DOI: 10.1152/ajplung.00184.2023
Mada Ghanem, Aurélien Justet, Madeleine Jaillet, Eirini Vasarmidi, Tiara Boghanim, Mouna Hachem, Aurélie Vadel, Audrey Joannes, Pierre Mordant, Agshin Balayev, Taylor Adams, Hervé Mal, Aurélie Cazes, Nicolas Poté, Arnaud Mailleux, Bruno Crestani

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic options. Fibroblast growth factor receptor-4 (FGFR4) is a known receptor for several paracrine fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have antifibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of transforming growth factor-β (TGF-β), endothelin-1, and platelet-derived growth factor (PDGF) on FGFR4 expression in human lung fibroblasts. We determined the effect of FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-β-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in Fgfr4-deficient (Fgfr4-/-) mice compared with wild-type littermates (WT) and after FGF401 treatment in WT mice compared with a control group receiving the solvent only. FGFR4 was decreased in IPF lungs, as compared with control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment with TGF-β, endothelin-1, and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-β1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in Fgfr4-/- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo.NEW & NOTEWORTHY FGFR4 has been reported to have antifibrotic effects in the liver. We aimed to determine the involvement of FGFR4 during IPF. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. To our knowledge, this is the first study to assess the profibrotic action of FGFR4 during pulmonary fibrosis.

导言 IPF 是一种破坏性肺病,治疗方法有限。FGFR4是已知的几种旁分泌型成纤维细胞生长因子(FGF)的受体。FGFR4 也是 FGF19 的主要受体,FGF19 是一种内分泌性 FGF,我们的研究小组已证实其在肺部具有抗纤维化特性。我们旨在确定 FGFR4 是否能调节肺纤维化。方法 我们评估了 IPF 和对照肺的 FGFR4 mRNA 和蛋白水平。在体外,我们测定了 TGF-b、内皮素-1 和 PDGF 对人肺成纤维细胞中 FGFR4 表达的影响。我们使用特异性药理抑制剂(FGF401)或在小鼠胚胎成纤维细胞(MEFs)中进行基因缺失来确定 FGFR4 抑制对 TGF-b 诱导的肌成纤维细胞分化的影响。在体内,我们评估了Fgfr4缺陷(Fgfr4-/-)小鼠与野生型小鼠(WT)相比,以及WT小鼠经FGF401处理后与仅接受溶剂的对照组相比,博莱霉素诱导的肺纤维化的发展情况。结果 与对照组相比,IPF 肺中的 FGFR4 在 mRNA 和蛋白质水平上都有所下降。在体外,经 TGF-β、内皮素-1 和 PDGF 处理后,FGFR4 下调。在体外,用 FGF401 抑制 FGFR4 可防止 TGF-b1 诱导的肺成纤维细胞胶原和 ACTA2 的增加。在 Fgfr4-/- MEFs 中也观察到了类似的结果。在体内,FGFR4 基因缺失或 FGFR4 药物抑制并不能调节博莱霉素诱导的肺纤维化。结论 我们的数据表明,FGFR4 在体外通过增强 TGF- β 信号传导发挥促纤维化特性。然而,抑制 FGFR4 并不足以阻止肺纤维化在体内的发展。
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引用次数: 0
Nanoparticles to target asthma. 针对哮喘的纳米粒子
IF 3.6 2区 医学 Q1 PHYSIOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-29 DOI: 10.1152/ajplung.00248.2024
Samantha K Hamrick, Michael A Thompson, Vincent M Rotello, Y S Prakash, Christina M Pabelick

Asthma is a heterogeneous chronic lung disease that affects nearly 340 million people globally. Airway hyperresponsiveness, remodeling (thickening and fibrosis), and mucus hypersecretion are some hallmarks of asthma. With several current treatments having serious side effects from long-term use and a proportion of patients with uncontrolled asthma, there is an urgent need for new therapies. With an increasing understanding of asthma pathophysiology, there is a recognized need to target therapies to specific cell types of the airway, which necessitates the identification of delivery systems that can overcome increased mucus and thickened airways. Nanoparticles (NPs) that are highly customizable (material, size, charge, and surface modification) are a potential solution for delivery systems of a wide variety of cargoes (nucleic acids, proteins, and/or small molecules), as well as sole therapeutics for asthma. However, there is a need to consider the safety of the NPs in terms of potential for inflammation, toxicity, nonspecific targets, and accumulation in organs. Ongoing clinical trials using NPs, some FDA-approved for therapeutics in other diseases, provide confidence regarding the potential safety and efficacy of NPs in asthma treatment. This review highlights the current state of the use of NPs in asthma, identifying opportunities for further improvements in NP design and utilization for targeting this chronic lung disease.

哮喘是一种异质性慢性肺部疾病,影响着全球近 3.4 亿人。气道高反应性、重塑(增厚、纤维化)和粘液分泌过多是哮喘的一些特征。由于目前的几种治疗方法在长期使用后会产生严重的副作用,而且有一部分患者的哮喘无法得到控制,因此迫切需要新的治疗方法。随着对哮喘病理生理学认识的加深,人们认识到需要针对气道中的特定细胞类型进行治疗,这就需要找到能够克服粘液增多和气道增厚的给药系统。可高度定制(材料、大小、电荷、表面修饰)的纳米颗粒(NPs)是多种货物(核酸、蛋白质和/或小分子)输送系统以及哮喘唯一疗法的潜在解决方案。然而,还需要考虑 NPs 的安全性,包括可能引起的炎症、毒性、非特异性靶点以及在器官中的蓄积。正在进行的使用 NPs 的临床试验(其中一些已获得美国食品及药物管理局批准用于其他疾病的治疗)为 NPs 在哮喘治疗中的潜在安全性和有效性提供了信心。本综述重点介绍了氮磷态物质在哮喘中的应用现状,并指出了进一步改进氮磷态物质设计和应用以治疗这种慢性肺部疾病的机会。
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引用次数: 0
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