呼吸内镜23-24：支气管胸膜瘘的气管镜表现，干细胞治疗方法 / 开普饭

呼吸内镜23：支气管亚段解剖的小诀窍

常记溪亭日暮，沉醉不知归路。

孙丹雄

破诗

对酒当歌，去日苦多！

人生一世，草木一秋！

前言

支气管胸膜瘘，就是支气管与胸膜搞外交，支气管的空气、细菌源源不断的进入胸膜腔！后果你懂的！

英文解释：Bronchopleural fistula is a pathologic connection between the airway and the pleural space that may develop after lung resection.

最主要的治疗方式还是手术修补支气管残端。

不能耐受手术，则支气管镜下封堵。

还是不行，则可考虑干细胞治疗。

干细胞实在太诱人了！前途无量！哈佛大学教授都忍不住为他作假！

我们不能因为哈佛教授作假就停止研究的步伐！

另外，干细胞叫“stem cell”，不叫“fuck cell”，记住了！

01 干细胞 VS 气功

干细胞不是气功，我觉得前途无量！虽然是路漫漫其修远兮！

什么情况？

气管镜表现

Panel A shows a flexible bronchoscopic view before bone marrow–derived mesenchymal stem-cell transplantation for the treatment of patency in the central part of the right bronchial stump (arrow), with a 3-mm orifice.

图A示右主支气管残端3mm瘘口（箭头）。注意看，箭头上方、瘘口内，可见缝合伤口的钛夹。

The patient underwent bone marrow aspiration followed by mesenchymal stem-cell isolation and expansion; bronchoscopy was performed, and 10 million autologous bone marrow–derived mesenchymal stem cells were injected into the pars membranacea of the right main bronchial stump as close as possible to the orifice of the fistula.

抽取患者自身骨髓，分离并培养骨髓间充质干细胞（bone marrow⁃derived mesenchymal stem⁃cell，BMSC），在气管镜下将1千万个骨髓间充质干细胞注射于右主支气管残端膜部，需尽量靠近瘘口的边缘。

Panel C shows the flexible bronchoscopy view 60 days after the infusion of mesenchymal stem cells, with visible healing of the central bronchial dehiscence and no evidence of the titanium staple on the external aspect of the suture (arrow).

图C显示干细胞注射60天后，支气管中央裂开处明显愈合，缝合线的外部没有钛钉的迹象（箭头）。

这篇文章发表在《新英格兰杂志》，虽然是“To the Editor”，但说明还是有一定价值。

PetrellaF. Airway fistula closure after stem-cell infusion[J]. N Engl J Med, 2015

03 国内报道

A 33-year-old woman with pulmonary cysts underwent a lobectomy to the right lower lobe. Six months after the lobectomy, she developed a cough and purulent expectoration, and a hydropneumothorax was detected by computed tomography (CT) scan. She, therefore, underwent a bronchoscopy, and a fistula of the size of 5 mm × 2 mm in the stump of the right lower lobe was confirmed.

33岁女性，因为肺囊肿行右下肺切除术，6月后诊断支气管胸膜瘘（5毫米× 2毫米）。

The fistula was ∼5 mm in diameter, at the baseline (black arrow).

瘘口约5毫米（箭头）。

An intercostal chest tube was placed in the right chest. The following therapeutic approaches were employed over a 2-year period, each of which failed to close the fistula: covered Y-type bronchial stent, self-made spigot, and local injection of platelet-rich plasma, fibrinogen, and thrombin.

在右胸放置了一根肋间引流管。在2年的时间里，采用了以下治疗方法，但每种方法都无法闭合瘘管，包括:Y型支架、自制塞子以及局部注射富血小板血浆、纤维蛋白原和凝血酶。

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Umbilical cord MSCs (1.1 × 10e7 cells/mL; a total of 2 × 10e7 cells/1.8 mL) were injected into the submucosa at the bronchial stump and into the granulation around the fistula through a flexible bronchoscope. Aseptic technique was strictly applied, to prevent infection. Simultaneously, umbilical cord mononuclear cells were intravenously injected (5 × 10e6 cells/mL; a total of 2 × 10e8 cells/100 mL).

脐带间充质干细胞(1.1 × 10e7个/mL;总共2 × 10e7个/1.8 mL) ，在气管镜下，注射到支气管残端瘘口周围的粘膜下、肉芽组织中。严格无菌操作。

同时，静脉给予脐带间充质干细胞（5 × 10e6 个/mL; 总共2 × 10e8 个/100 mL）。

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Eight days after MSC administration, the fistula diameter was ∼2 mm.

8天后，瘘口由5毫米，减少至2毫米。

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At 1 month and 3 months, the walls of the fistula were covered with epithelium and vessels similar to fresh granulation tissue.

治疗后1月和3月复查，瘘口闭合，瘘口壁见上皮组织、血管覆盖。类似新鲜肉芽组织。

随访半年无复发。

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曾奕明, et al. Closure of Bronchopleural Fistula with Mesenchymal Stem Cells: Case Report and Brief Literature Review[J]. Respiration, 2018.

04 支气管镜下注射干细胞

Bronchoscopic images of the endobronchial (arrowhead) and pleural (arrow) fistulous openings showed a fistula measuring approximately 5 mm Å ~ 6 mm (B and C).

瘘口5~6毫米，图B示支气管镜下表现，图C示胸膜侧表现。

After several surgical and bronchoscopic interventions to close the BPF were attempted without success, an open-window thoracostomy was performed. Two years later, the patient underwent resection of a single liver metastasis followed by adjuvant chemotherapy.

尝试了几次外科手术和支气管镜介入治疗，瘘口仍然没有愈合。后来进行了开窗胸廓造口术，持续引流。两年后，患者接受了单个肝转移瘤切除术，随后进行了辅助化疗。

A bronchopleural fistula was identified through bronchoscopy, and the mucosa surrounding the fistula was ablated with an argon plasma coagulator. Isolated stem cells were then endoscopically injected into the de-epithelialized area and fistulous tract.

If an open thoracostomy was present at the time of the intervention, the same procedure was performed on the pleural side.

通过支气管镜检查发现支气管胸膜瘘，用氩气刀消融瘘周围的粘膜。然后将分离的干细胞通过支气管镜注射到去上皮区和瘘管中。如果在介入治疗时进行了开胸造口术，则在胸膜侧进行同样的操作。

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精彩英文：Bronchoscopic follow-up was scheduled weekly during the first month, monthly during the first year, and then yearly.

支气管镜随访计划在第一个月每周进行，第一年每月进行，然后每年进行。

The 3-year follow-up revealed a successful and maintained fistula closure, no treatment-related adverse reactions, nonlocal malignant recurrence and improved quality of life.

3年的随访显示瘘管闭合成功并保持，无治疗相关的不良反应，无局部恶性肿瘤复发，生活质量提高。

Díaz-AgeroÁPJ. Novel bronchoscopic treatment for bronchopleural fistula using adipose-derived stromal cells[J]. Cytotherapy, 2016.

05 外科手术置入干细胞

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(A): Preoperative bronchoscopy demonstrating large bronchopleural fistula (BPF) cavity and lateral extension of fistula tracts.(B):Postoperative bronchoscopy (3 months) demonstrating progressive healing of BPF site.

图A:术前支气管镜检查显示大支气管胸膜瘘(BPF)腔和瘘道的横向延伸。图B：术后支气管镜检查(3个月)显示BPF部位逐渐愈合。

Adipose-derived MSCs were isolated from patient abdominal adipose tissue, expanded, and seeded onto bio-absorbable mesh, which was surgically implanted at the site of BPF.

脂肪来源的间充质干细胞从患者腹部脂肪组织中分离，扩增，接种到生物可吸收网上，并通过外科手术植入在瘘口中。

这是个巨大支气管胸膜瘘（大约1.5厘米），干细胞治疗后愈合，牛啤否？具体肿么一回事？

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63岁女性，因“巨大右主干支气管胸膜瘘（大约1.5厘米）”来诊。
A 63-year-old woman was referred for treatment of a large right mainstem BPF (approximately 1.5 cm) temporized with an Eloesser window and wound packing.
曾因T3N0M0肺鳞癌行“右肺切除术+胸壁切除术”，术后30天出现支气管胸膜瘘。
She had previously undergone a right pneumonectomy and chest wall resection for a T3N0M0 squamous cell carcinoma and developed a BPF approximately 30 days after the initial operation.
暂时采用Eloesser皮瓣，进一步行胸壁切除，改变敷料控制败血症。
This was temporized with an Eloesser flap, further chest wall resection, and dressing changes for control of sepsis.
虽然给予最好的处理，但是支气管胸膜瘘还是反复出现。
Despite best management, her BPF subsequently recurred.
大约一共搞了30次支气管镜和外科手术来治疗支气管胸膜瘘，但是都没有成功，包括修复、大网膜瓣覆盖、气管支架置入和支气管镜手术。
Combined, approximately 30 bronchoscopic and surgical attempts at either closure or management of complications of the resulting BPF were unsuccessful, including primary repair, omental flap coverage, tracheal stent placement, and bronchoscopic approaches.
在用尽所有治疗选择，并考虑到患者的健康每况日下之后，我们开始使用自体MSC植入的基质移植物和外科手术相结合的方法来修复缺损。
After exhausting therapeutic options, and considering the patient’s declining health, we moved toward using an autologous MSC-seeded matrix graft in combination with a surgical procedure to repair the defect

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脂肪间充质干细胞
Adipose-Derived Mesenchymal Stem Cells
给病人行腹壁脂肪活检术。
The patient underwent an abdominal wall adipose biopsy during bronchoscopic evaluation of the fistula.
在病人右侧腹壁切除取到0.6g无菌脂肪。
A small incision was made on the right side of the patient’s abdominal wall, and under sharp dissection, 0.6 g (approximately 0.67 ml) of aseptically obtained adipose tissue was transferred sterilely to a container.
在无菌活检组织上立即分离MSCs（间充质干细胞）。
Immediate isolation of MSCs was performed on the aseptically biopsied tissue.
简单地说，组织在Dulbecco的磷酸盐缓冲盐水（D-PBS）中洗涤，离心，切碎，并在D-PBS溶液中的0.075%胶原酶中培养60分钟。
Briefly, tissue was washed in Dulbecco’s phosphate-buffered saline (D-PBS), centrifuged, minced, and incubated in a 0.075% collagenase in D-PBS solution for 60 minutes.
MSCs（间充质干细胞）在所有释放标准下均呈阴性，给药前未分化。

The MSCs were found to be negative for all release criteria and were not differentiated before administration.

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瘘管闭合手术
Surgical Approach for Fistula Closure
再次行开胸手术。
A redo right thoracotomy was performed, and the right mainstem bronchus was identified and dissected free to expose and resected flush with the carina.
再次做右开胸手术，确认右主干支气管，使其裸露并切除与隆起齐平;使用间断的3-0 Vicryl缝线关闭气道;在放置前，将经MSC接种的基质修剪至最佳状态用3-0 Vicryl缝线将基质固定在闭合部位上的位置，收集腹部游离皮瓣并用于消除胸膜空间。重复性支气管镜检查，以确认闭合的完整性和气道通畅性。
A redo right thoracotomy was performed, and the right mainstem bronchus was identified and dissected free to expose and resected flush with the carina.The airway was closed using interrupted 3-0 Vicryl sutures.Before placement, the MSC-seeded matrix was trimmed for optimal fit into the affected area.The matrix was anchored in position over the closure site with 3-0 Vicryl sutures.An abdominal free flap was harvested and used to obliterate the pleural space.Repeat bronchoscopy was performed, confirming integrity of the closure and airway patency.
手术结束后，病人再次进行了气管造口术，以便于术后的通气和分泌物管理。术后第17天拔管，术后25天出院，情况良好。支气管镜检查（3个月）、胸部电脑断层扫描和18个月的临床随访均显示瘘管愈合良好。患者临床表现良好，夜间采用正压通气，已恢复日常生活活动。
After surgical closure, the patient underwent redo tracheostomy to facilitate postoperative ventilation and secretion management. She was decannulated on postoperative day 17 and discharged home in good condition on postoperative day 25. Surveillance bronchoscopy (3 months) (Fig. 3), computed tomography scan of the chest (16 months), and clinical followup at 18 months have demonstrated the fistula to be well healed. The patient is doing clinically well, uses positive pressure ventilation at night, and has resumed her activities of daily living.

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AhoJM. Closure of a Recurrent Bronchopleural Fistula Using a Matrix Seeded With Patient-Derived Mesenchymal Stem Cells[J]. Stem Cells Transl Med, 2016.

question

我有一个疑问，支气管胸膜瘘形成，我们身上的干细胞毫无作为，为什么把他们直接送到瘘口周围，他们就开始干活了？

干细胞是买不起车票么？还是晕船，不能随着血液进入瘘管修复？

为什么非得用八抬大轿把他们注射到瘘口，他们才上班？

这些报道，或许很可能是巧合！

干细胞治疗肺部疾病，万里长征才开始吧？！

干细胞，就像一个婴儿，将来可能是国家主席，也可能是普通老百姓；可能是乞丐，也可能是亿万富翁；可能是律师，也可能是小毛贼......

干细胞，按照发育阶段分类，主要分为两大类：

胚胎干细胞和成体干细胞。

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胚胎干细胞是指来源于囊胚的内细胞团。
成体干细胞是从许多组织中分离出来的干细胞。
成体干细胞中运用最广的为间充质干细胞（mesenchymal stem cell，MSC），可存在于骨髓、脂肪、血液、脐带等多种组织中。
来源于骨髓、具有高度的自我更新和分化潜能的细胞群，统一命名为骨髓间充质干细胞（bone marrow⁃derived mesenchymal stem⁃cell，BMSC），具有取材方便、免疫原性弱、可进行自体移植等诸多优点，在不同的诱导环境下，可分化为成骨细胞、成软骨细胞、上皮细胞、神经细胞、内皮细胞及心肌细胞等多种组织细胞。

杨柳岸，晓风残月。

视频

支气管解剖

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呼吸内镜23-24：支气管胸膜瘘的气管镜表现，干细胞治疗方法

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