肺淋巴管平滑肌瘤病

目的　提高对罕见病肺淋巴管平滑肌瘤病 (PL AM)的认识。方法　对我院诊治的患者进行分析 ,并结合文献复习。结果　 PL AM是一种罕见的弥漫性肺部疾病 ,临床反复发作自发性气胸或 /和乳糜胸、活动后呼吸困难和痰血等。肺功能呈阻塞性或混合性通气功能障碍 ,低氧血症。胸部 X线表现为两肺弥漫分布网格状阴影 ,高分辨 CT(HRCT)示弥漫分布囊状改变。病理学检查示 :肺组织淋巴管增生和扩张 ,管外平滑肌明显增生。结论　育龄期妇女如反复发生气胸及出现原因不明的呼吸困难、咯血或乳糜胸 ,应疑诊 PL AM,及时行 HRCT及肺功能检查 ,必要时肺活检 ,以明确病理诊断。     

肺淋巴管平滑肌瘤病的研究新进展

肺淋巴管平滑肌瘤病是一种罕见的弥漫性肺部疾病.随着对该病研究的不断深入,目前对其发病机制有了更进一步的认识.该病的发生被认为与TSC1或TSC2基因的突变有关,而这可能为该病的治疗提供新的方向.     

肺淋巴管平滑肌瘤病

目的 提高对罕见病淋巴管平滑肌瘤病（ＰＬＡＭ）的认为。方法 对１９９２年对来诊治的３例ＰＬＡＭ患者的临床资料进行分析,并结合文献复习。结果 ＰＬＡＭ是一种罕见的弥漫肺部疾病,临床表现为反复发作自发性气胸、活动后呼吸困难和痰血等。肺功能呈阻塞性或混合性通气功能障,动脉血气示低氧血症。胸部Ｘ线表现为两肺弥漫分布网格状影,高分辨ＣＴ（ＨＲＣＴ）示两肺弥漫分布囊状改变。病理学检查示肺组织淋巴管增生和扩张,     

肺淋巴管平滑肌瘤病发病机制的研究进展

肺淋巴管平滑肌瘤病是一种罕见的肺部疾病,目前其发病机制尚未完全阐明。本文通过回顾近年来相关文献,从与结节性硬化基因的相关性、雌激素的相关性以及该细胞特性等方面以求了解该病的研究进展。     

肺淋巴管平滑肌瘤病一例

正肺淋巴管肌瘤病(pulmonary lymphangioleiomyomatosis,PLAM)是一种罕见的弥漫性肺部疾病,绝大多数发生于育龄期妇女,亦有男性患者报道。本疾病发病率大约为1/100万。表现为不典型增生的平滑肌细胞侵袭肺组织,以进行性呼吸困难、反复气胸及乳糜胸为主要临床表现,最终因呼吸衰竭死亡。由于罕见而散发,且临床表现多样,常被误诊,现将我科收治的1例PLAM患者的临床资料进行报道,以提高对该病的认识,减少误诊和漏诊。     

肺淋巴管平滑肌瘤病1例

<正>病例资料患者女性,37岁,因胸痛1 d就诊。患者既往有腹膜后异常淋巴结手术史,腹腔引流大量乳糜液。并多次在外院诊断为多发性肺囊肿。入院查体:T 36.4℃,P62次/min,R23次/min,Bp 125/80 mmHg,双肺呼吸音粗,双肺未闻及明显啰音,心肺腹及四肢无异常。入院辅检:血常规、肝肾功能、电解质、血糖、心肌酶谱、肌钙蛋白均正常。肺CT双肺弥漫     

肺淋巴管平滑肌瘤病

淋巴管平滑肌瘤病 (lymphangiolaiomyomatosic,LAM)是一种女性育龄期的少见病。自 1937～ 1997年60年间世界仅陆续报告了 30 0余例。由于罕见与散发 ,又缺少动物模型与组织培养不能深入研究。病因不明 ,亦缺少有效的治疗方法。病情进行性发展 ,最终死于慢性呼吸衰竭。提高对 LAM的诊断水平十分必要。我院两年间确诊两例 ,现结合文献进行讨论。例一　女性、4 0岁 ,1996年出现逐渐加重的呼吸困难与咳嗽 ,有少许白粘痰 ,时常痰中带血。一年后病情加重 ,胸片见弥漫性小结节、网纹增加 ,肺体积不缩小。CT见均匀分布大小不等的薄壁囊肿 ,并见…     

肺淋巴管平滑肌瘤病的临床分析

目的探讨肺淋巴管平滑肌瘤病(LAM)的临床特征,治疗和预后。方法回顾性分析1例LAM病人并复习文献78例。结果全部79例患者中,女性占多数74例(93.7%)。发病年龄:69例(87.3%)为育龄期妇女,均经肺组织活检病理确诊。临床表现为呼吸困难(75例),咯血(40例),气胸(38例),乳糜胸(24例),行胸部高分辩CT(HRCT)扫描63例,均显示两肺弥漫性薄壁囊状阴影;行肺功能检查45例,阻塞性通气功能障碍32例,混合性通气功能障碍9例,行血气分析43例,其中低氧血症41例,型呼吸衰竭2例;给予安宫黄体酮及其他药物治疗32例,其中死亡或病情加重19例,其中11例从确诊到死亡时间为0.5-3.5年。结论LAM以呼吸困难,咯血、气胸和乳糜胸为主要临床特征,安宫黄体酮疗效不理想。     

雌激素在肺淋巴管平滑肌瘤病发病机制中的研究进展

肺淋巴管平滑肌瘤病是一种罕见的弥漫性的肺部疾病,病因未明,目前尚无有效的治疗方法。现已发现肺淋巴管平滑肌瘤病几乎只发生于育龄期的女性,与体内雌激素水平密切相关,但是目前雌激素对肺淋巴管平滑肌瘤病的作用机制尚未完全清楚。本文就新近的研究结果阐述雌激素的作用机制,为肺淋巴管平滑肌瘤病的治疗提供新的方向。     

肺淋巴管平滑肌瘤病

淋巴管平滑肌瘤(lymphangioleiomyomatosis，LAM)，最早出现于Burell和Ross于1937年的病例报告中，在一例36岁的死亡妇女尸检中发现其肺呈蜂窝状，伴有左侧乳糜胸，淋巴结组织平滑肌增生。Von Stossel在同年也有类似病例报道。到目前为止已有超过300例的病例报道，每年世界范围内约有100例新发患。     

120例肺淋巴管平滑肌瘤病临床分析

目的通过分析中国大陆肺淋巴管平滑肌瘤病（PLAM）临床资料及误诊情况,以期提高医生对PLAM的认识。方法运用中国学术期刊全文数据库搜索截至2008年底由中国大陆学术期刊所发表的有关PLAM病例的文献,进而分析病例资料。结果120例入组患者确诊时的平均年龄是（37．26±6．40）岁。患者从出现症状到确诊平均需要（29．55±35．76）个月。该病患者临床表现多样,胸片无特征性改变。有10例患者合并肾血管平滑肌脂肪瘤,16例存在腹膜后肿块或淋巴结肿大。有64例患者在确诊前曾被误诊,易被误诊为特发性问质性肺炎或特发性气胸。结论需要进一步提高医生对PLAM的认识,以期减少误诊。     

肺淋巴管平滑肌瘤病九例临床和病理分析

目的 探讨肺淋巴管平滑肌瘤病(pulmonary lymphangionleiomyomatosis,PLAM)的临床和病理特征,提高临床诊治水平.方法 对广州呼吸疾病研究所确诊的9例PLAM患者的临床特点、影像学表现、肺功能及病理学检查进行分析并结合文献复习.结果 9例PLAM患者均为育龄期妇女(20～50岁),临床症状表现为呼吸困难(8/9)、咳嗽(6/9)、咯痰(2/9)、咯血(2/9)、胸痛(3/9)、自发性气胸(6/9)、乳糜胸(3/9)、乳糜性腹腔积液(2/9).胸部X线检查4例表现为双肺弥漫性网状结节影,2例表现为液气胸,2例表现为胸腔积液,1例表现为多发肺小囊状透光区及肺大疱,1例无异常.高分辨率CT具有特征性变化,9例双肺均可见多发小囊状影,直径2～20 mm,壁较薄.2例腹部CT于腹主动脉前可见多个肿大的淋巴结.6例患者进行了肺功能检查,3例通气功能正常,1例呈中度阻塞性通气功能障碍,1例呈重度混合性通气功能障碍,1例呈极重度混合性通气功能障碍,其中1例支气管舒张试验阳性.4例肺弥散功能下降.4例(4/9)经纤维支气管镜肺活检,5例(5/9)经胸腔镜活检,全部经病理确诊.病理学检查显示不同成熟度平滑肌细胞在细支气管壁、肺泡壁、淋巴管壁和血管壁周围增生,肺实质呈囊性变.结论 PLAM表现不典型,易被漏诊、误诊,应提高对本病的认识.     

Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis

Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography–mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 (Tsc2) mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.

The use of messenger RNA (mRNA) for vaccination (1, 2), protein replacement therapy (3) and cancer immunotherapy (4), and mRNA technology encoding CRISPR/Cas nuclease for genome editing (5) holds the potential to revolutionize the treatment of a wide range of currently untreatable genetic diseases. The US Food and Drug Administration (FDA) recently authorized two mRNA vaccines enabled by nonviral lipid nanoparticles (LNPs) against COVID-19 for emergency use, representing a key milestone in mRNA therapeutics. Aside from COVID-19, other mRNA vaccines against influenza viruses (6), Cytomegalovirus (7), and advanced melanoma (8) have also been developed and are now in human clinical trials. The clinical success of these transformative therapeutics is largely reliant on the development of safe, efficient, and highly selective delivery systems to target mRNA toward specific tissues and cell types (9, 10).As one of the most advanced nonviral synthetic nanoparticles, LNPs have been proven to specifically deliver small interfering RNA (siRNA) to the liver for the treatment of hereditary transthyretin amyloidosis (11). Since mRNA predominantly accumulates in the liver and spleen following systemic delivery (12–16), much of the clinical interest to date has focused on hepatic diseases. Delivery vehicles that enable specific mRNA delivery to extrahepatic tissues are urgently needed to fully realize the potential of mRNA-based therapy. Considerable effort has been made to develop organ-targeted LNPs to bypass liver accumulation by modifying the surface of LNPs with targeting moieties such as peptides, antibodies, and proteins (17–19). Recently, targeted LNPs functionalized with alpha plasmalemma vesicle–associated protein antibody were developed for lung-targeted mRNA delivery in vivo (18). More recently, a selective organ targeting (SORT) strategy was developed to engineer LNPs to tune the biodistribution of LNPs; the incorporation of an extra excipient, the SORT molecule, can enable the precise alteration of the in vivo mRNA delivery profile (20). These strategies exhibit advantages in mitigating liver accumulation and delivering mRNA to lungs or spleens. These promising developments motivate us to continue explore innovative ways to deliver mRNA to specific locations.A major roadblock in the development of targeted LNPs is difficulty predicting the in vivo targeting behavior of newly designed LNPs due to the limited understanding of the nano-bio interactions between nanoparticles (NPs) and biological components. The outer surface of NPs can be rapidly covered with a layer of serum proteins, referred to as the “protein corona,” which remodels the surface property of NPs and substantially affects the interaction of NPs with organs and cells (21). We and others have demonstrated that the lipidoid amine head structure can impact the delivery efficacy and even the in vivo targetability of mRNA-loaded LNPs (22–24). In a recent study, we showed that imidazole-based synthetic lipidoids preferentially target mRNA to the spleen (25). For the lipidoid tail chemistry, although considerable progress has been made in the understanding of lipidoid tail length, degree of unsaturation, and degree of branching on the effect of mRNA delivery potency (26–29), the influence of lipidoid tail structures on the in vivo selectivity of LNPs remains poorly understood. To address this important knowledge gap, we synthesized a library of amide bond–containing lipidoids (N-series LNPs) via Michael addition reaction between amine heads and acrylamide tails (Fig. 1A). Surprisingly, from in vivo screening, we found that the N-series LNPs almost exclusively deliver mRNA to the lung following systemic administration (Fig. 1 B and C). Intriguingly, our previous study demonstrated that the O-series lipidoids, which contain an ester bond in the tails, tend to deliver mRNA into the liver (16). To better understand why such a small change induces such striking organ specificity, we further investigated the underlying mechanisms of these delivery differences. We hypothesized that once injected into the bloodstream, the LNPs can selectively govern the adsorption of specific plasma proteins to serve as targeting ligands that direct LNPs to selected organs. Indeed, using proteomics, we identified a group of unique plasma proteins specifically absorbed on the surface of two representative LNP candidates, 306-O12B and 306-N16B, that may affect the targetability of these LNPs. More importantly, we found that different pulmonary subcellular populations can be targeted by changing the lipidoid head structure of N-series LNPs. Furthermore, we evaluated the lung-targeting LNPs for the in vivo targeted delivery of Tsc2 mRNA to TSC2-deficient cells to restore the expression of the TSC2 tumor suppressor for the treatment of pulmonary lymphangioleiomyomatosis (LAM), a rare genetic disorder caused by biallelic mutations and loss of function of TSC complex genes. This study provides proof of concept that tuning the in vivo organ-targeting behavior of LNPs can be achieved by tailoring the composition of protein corona via simple chemistry. This work provides a strategy for the rational design of highly specific organ- and cell-selective LNPs for mRNA-based therapy.Open in a separate windowFig. 1.Synthesis and in vivo screening of N-series LNPs. (A) Synthetic route and representative chemical structure of lipidoids. Representative whole-body bioluminescence images of mice (B) and in vivo mRNA delivery efficacy (C) of N-series LNPs measured by the IVIS imaging system. Mice were injected with either of the Luc mRNA–loaded N-series LNPs at a single dose of 0.5 mg/kg. Images were taken at 6 h postinjection (n = 3). Data are presented as mean ± SD; the error bar around each data point is the SEM.     

肺淋巴管平滑肌瘤病1例并文献复习

目的探讨肺淋巴管平滑肌瘤病（PLAM）的临床特征、疗效和预后,提高对该病的认识。方法回顾性分析1例PLAM病人的临床资料,并复习文献。结果该病主要发生于育龄期妇女,临床症状无特异性,以咳嗽、胸闷、气短和呼吸困难为主;常发生乳糜胸和（或）气胸;肺功能检查有弥散功能下降,以阻塞性通气功能障碍为多,兼有限制性通气功能障碍;HRCT见双肺弥漫薄壁囊状阴影为影像学特征性表现;肺组织活检是确诊的主要依据。结论本病病因目前尚不清,孕激素疗效不理想,有待进一步探讨病因及寻找有效的疗法。     

肺淋巴管肌瘤病11例报告并文献复习

目的 探讨肺淋巴管肌瘤病( PLAM)的临床和预后.方法 分析经治的11例PLAM病人的资料,并复习文献.结果 11例均为女性;年龄31 ～55岁,平均(44±9)岁;均经肺组织活检明确病理;主要临床表现为进行性呼吸困难10例(发生率91％),咳嗽6例(55％),咯血2例(18％),乳糜胸3例(27％),气胸3例(27％)等;11例患者均进行肺功能检测,均有弥散功能下降,9例行动脉血气分析,其中7例表现为低氧血症,4例合并呼吸衰竭;11例行胸部高分辨率CT (HRCT),均显示两肺弥漫性薄壁囊状阴影.结论 PLAM以呼吸困难,咳嗽,气胸和乳糜胸为主要临床表现;双肺弥漫性薄壁囊状阴影为影像学特征表现;肺组织活检是确诊的主要依据.