COVID-19関連追加(2021116日)

★当院HP関連ファイル:

2020527日(COVID-19の血管新生Angiogenesisについて)

202195日(肺内シャントについて)

COVID-19肺炎の気管支循環】

Ackermann M, et al. The Bronchial Circulation in COVID-19 Pneumonia. Am J Respir Crit Care Med. Received: March 10, 2021 Accepted: November 03, 2021.

https://doi.org/10.1164/rccm.202103-0594IM.

 

重症COVID-19の生命を脅かす肺病変は主として,肺内皮炎(pulmonary endothelialitis),微小血管症(microangiopathy),異常血管新生(aberrant angiogenesis)によって特徴づけられる(1).肺循環における顕著な微小血管症は多くの研究で強調されているが,気管支循環の影響は十分に解明されていない.そこで我々は,男性3人の重症COVID-19患者(年齢63.7±14.2, 入院期間22±1, 機械式人工呼吸を受けていた)の肺葉全体を,conventional CT,組織学,微小血管樹脂鋳造法(microvascular corrosion casting),hierarchial位相コントラストXCTHiP-CT: hierarchial phase-contrast tomography)を用いて総合的に解析した(2).我々は,フランスのGrenobleにあるFrench Alps Laboratory of AnatomyLADAF)の献体者(年齢78.3±13.6, 非人工呼吸, 女性2, 男性1人が脳卒中または子宮癌で死亡)の3つの対照肺を使用した.

CTアンギオグラフィにおいて,我々は,報告されているCOVID-19肺傷害の肺後遺症が、両側の末梢GGObilateral, peripheral ground-glass opacities),気管支周囲のコンソリデーション(peribronchial consolidations)、末梢の肺血管うっ血(peripheral macrovascular congestion)という形で見られた(3)Fig.1A,B).気管支周囲および血管周囲の微小血管[vasa vasorum: 血管壁栄養血管]は明瞭に拡張していたFig.1C-Fこの気管支循環による肺内シャントFig.2A)は,炎症,ARDS,慢性血栓塞栓症などの様々な気道の状態において,継続的な灌流を説明するものである(3).重症COVID-19肺炎では,気管支周囲血管の微小血管構造(microvascular architecture of the peribronchial vessels)には,異常な血管束が密集した微小血管構造(microvascular architecture with densely packed aberrant bundles of blood vesselsが見られた(Fig.2B-E).peribronchial plexusの拡大は,transluminal endothelial tissue pillarsの出現によって証明されるように,主にintussusceptive angiogenesisIA: 嵌入性血管新生)によってもたらされる(Figure 2B-D(1,4,5)

COVID-19肺炎における気管支周囲血管をHiPCTによって空間的解析を行ったところ,気管支周囲および血管周囲の動脈ー静脈吻合部(arterio-venous anastomoses)の拡大,そして個々の肺二次小葉(secondary pulmonary lobules)を横断する「Sperrarterien」(blockade arteries※閉塞動脈)のリクルートが初めて3次元的に確認された(Figure 3A, 3B and supplemental movieこの肺小葉内シャント(intralobular shuntingは,糸球体のような血管拡張の異なるスポット(different spots of glomerouid-like vascular expansion)を伴う(Figure 3C and D

ここで我々は,COVID-19における気管支肺シャント(bronchio-pulmonary shuntingの複雑な3次元現象(complex three-dimensional phenomenon)を初めて明らかにした.しかし,この過剰な新生血管形成の後遺症,すなわち領域内の過灌流(intralesional hyperperfusion)および長期的な影響の原因となる可能性のある実際のリモデリングについては,これまでのところ理解されていない

 

Figure 1: Bronchial artery and vasa vasorum dilatation and expansion in COVID-19 pneumonia. (A) Dual energy computed tomography (CT) revealed the characteristic features of a severe COVID-19 pneumonia as bilateral ground-glass opacities, peribronchial consolidations and a diffuse crazy-paving pattern. (B) Iodine map showed dilatation of macro-vessels in or leading to opacified air spaces and frequently evident vascular "tree-in-bud" (blue arrows). Hierarchical phase-contrast tomography (High-resolution tomographic images analyzed by Synchrotron radiation X-ray tomographic microscopy HiP-CT) demonstrating the regular architecture in healthy control lungs (C), whereas in Covid-19 pneumonia a dilatation and an expansion of vasa vasorum and peribronchial vessels was observed (D); br: bronchus, vs: pulmonary vessel, ad: alveolar duct; scalebar: 1000 µm (C), 400µm (D). Representative HE-stained sections show sporadic peribronchial vessels (black arrow) in the control tissue (E), whereas the peribronchial plexus in Covid-19 lungs was characterized by an expansion and the formation of angiomatoidand plexiformlike vessels (black arrow). vs: blood vessel, br: bronchus ; scalebars: 200 μm (E), 100 μm (F).

 

 

 

 

Figure 2: Intrapulmonary shunting via bronchial circulation in COVID-19 pneumonia. (A) Schematic illustrates intrapulmonary cross-circulation and draining by bronchial arteries to the peripheral lung, pleurohilar veins and to “Sperrarterien”, specialized, spiral-like intrapulmonary arteriovenous anastomoses recruited by hypoxia and flow irregularities. The bronchial circulation arises primarily direct from the thoracic aorta and intercostal arteries and, under normal conditions, constitutes less than 2% volume of the left cardiac output. However, the bronchial flow can significantly exceed the regular hemodynamics upon hypoxic and inflammatory stimulus. As part of a physiological right-left shunting, nearly twothird of the bronchial vessels are drained peribronchially to the peripheral lung and finally into the left ventricle (up to 4% of left ventricular output), whereas the remaining third is perfused pleuro-hilar veins draining ultimately to the right heart (B) Scanning electron micrograph of a microvascular corrosion cast demonstrates the expansion of vasa vasorum of an intralobular artery by intussusceptive angiogenesis in lung tissue of a patient succumbed to severe COVID-19 pneumonia; scalebar: 50µm. Intussusceptive angiogenesis is a wellcharacterized morphogenetic process observed during the capillary expansion in cancer, inflammation, and regeneration, but has also been reported in the alveolar plexus of COVID-19 lungs; br: bronchiole, ad: alveolar duct; scalebar: 100µm. (C) Scanning electron micrograph of a microvascular corrosion cast demonstrates the peribronchial plexus in health control lungs (blue arrows); scalebar: 200 µm. (D) Scanning electron micrograph of a microvascular corrosion cast reveals the crosscirculation in Covid-19 lung tissue between a Sperrarterie (sa) and a lobular artery (pa) in a secondary pulmonary lobule which is characterized by plexiform-like vascular proliferations by intussusceptive angiogenesis (red arrowheads); br: bronchiole; scalebar: 200 µm. (E) Three-dimensional evaluation of microvascular corrosion casts by Synchrotron radiation X-ray tomographic microscopy illustrating the irregular, hierarchial vascularity with dilated, blunt-like vessels in COVID-19 pneumonia; scalebar: 100µm.

 

A: @70% peripheral lung, A30% pleurohilar veins, BSperrarterien= spiral-like intrapulmonary arteriovenous anastomoses. microthormbi, pulmonary circulation, bronchus, bronchial circulation.

これは,気管支動脈から末梢肺,pleurohilar veinへ,そして低酸素やflow irregularitiesによって生じる特殊な螺旋状の肺内気管支肺動脈吻合(spiral-like intrapulmonary arteriovenous anastomoses)である "Sperrarterien "への肺内循環と排出を模式的に示している.気管支循環は,主に胸部大動脈および肋骨間動脈から直接生じ,正常な状態では,左心拍出量の2%未満の容量を構成する.しかし,低酸素や炎症などの刺激を受けると,bronchial flowは通常の血行動態を大きく上回ることがある.生理的な右-左シャントの一部として,気管支血管の約3分の2は末梢肺に,最終的には左心室に排出される(左心拍出量の4%まで)が,残りの3分の1pleurohilar veinを還流し,最終的には右心に排出される.

 

 

 

Figure 3: Three-Dimensional complexity of vascular remodeling and bronchiopulmonary shunting in COVID-19 highlighted by Hierarchical Phase-Contrast Tomography (HiP-CT). (A) The distal bronchiole (blue) is paralleled by a centrilobular pulmonary artery (red) and an expanded plexus of private vessels (vasa vasorum) (yellow) in a secondary pulmonary lobule in the periphery of the left lower lobe; scalebar:4mm. (B) Dilatation and expansion of the peribronchiolar plexus and vasa vasorum (yellow) is observed around the distal terminal bronchiole (blue) and centrilobular pulmonary artery (red); scalebar: 1.3mm. (C) Numerous arteriovenous anastomoses (yellow) form between bronchial arteries and pulmonary artery drain into a pulmonary vein accompanied by a pronounced shunting of a Sperrarterie (white arrow). These specialized arteries are essential for intrapulmonary arteriovenous shunting and are located mainly at the septal margin of secondary pulmonary lobules where up to 3 to 5 such "Sperrarterien" anastomoses can be found in each lobule; scalebar: 0.7mm. (D) The perivascular vasa vasorum and bronchial vascular plexus are characterized by complex nodular lesions with angiomatoidand plexiform-like arrangements (white arrowheads); scalebar: 0.7mm. For high resolution details, see supplemental movie Covid-19 pneumonia. (E) In controls, the vascular architecture shows a well-organized hierarchy of peribronchial vessels; scalebar: 1.3mm. (F) Only few perivascular vasa vasorum are observed in healthy control tissue; scalebar: 0.7mm. For high resolution details, see supplemental movie control.

 

 

 

 

References

1) Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 Jul 9;383(2):120-128. doi: 10.1056/NEJMoa2015432. Epub 2020 May 21.

2) Walsh C, Tafforeau P, Wagner WL, Jafree DJ, Bellier A, Werlein C, Kühnel MP, Boller E, Walker-Samuel S, Robertus JL, Long DA, Jacob J, Marussi S, Brown E, Holroyd N, Jonigk DD, Ackermann M, Lee PD. Multiscale three-dimensional imaging of intact human organs down to the cellular scale using hierarchical phase-contrast tomography. bioRxiv [Preprint]. 2021 Feb 3:2021.02.03.429481. doi: 10.1101/2021.02.03.429481.

3) McCullagh A, Rosenthal M, Wanner A, Hurtado A, Padley S, Bush A. The bronchial circulation--worth a closer look: a review of the relationship between the bronchial vasculature and airway inflammation. Pediatr Pulmonol. 2010 Jan;45(1):1-13. doi: 10.1002/ppul.21135.

4) Eldridge L, Wagner EM. Angiogenesis in the lung. J Physiol. 2019;597(4):10231032. doi:10.1113/JP275860.

5) Ackermann M, Mentzer SJ, Kolb M, Jonigk D. Inflammation and intussusceptive angiogenesis in COVID-19: everything in and out of flow. Eur Respir J. 2020 Nov 12;56(5):2003147. doi: 10.1183/13993003.03147-2020.