Intrapulmonary vascular shuntpathways in alveolar capillarydysplasia with misalignmentof pulmonary veins

AbstractAlveolar capillary dysplasia with misalignmentof pulmonary veins (ACD/MPV) is a lethalneonatal lung disease characterised by severepulmonary hypertension, abnormal vasculatureand intractable hypoxaemia. Mechanismslinking abnormal lung vasculature with severehypoxaemia in ACD/MPV are unknown. Weinvestigated whether bronchopulmonaryanastomoses form right-to-left shunt pathwaysin ACD/MVP. We studied 2 infants who diedof ACD/MPV postmortem with direct injectionsof coloured ink into the pulmonary artery,bronchial artery and pulmonary veins.Extensive histological evaluations includedserial sectioning, immunostaining and 3-dimensional reconstruction demonstratedstriking intrapulmonary vascular pathwayslinking the systemic and pulmonary circulationsthat bypass the alveolar capillary bed. Thesedata support the role of prominent right-to-leftintrapulmonary vascular shunt pathways in thepathophysiology of ACD/MPV.

Alveolar capillary dysplasia with misalign-ment of pulmonary veins (ACD/MPV) is arare and lethal neonatal lung diseaseassociated with severe respiratory failureand pulmonary hypertension.1 Despiteimproved respiratory care, infants withACD/MPV die of sever hypoxaemia afterbirth.2 Abnormal vascular lung histology ofACD/MPV includes dysplastic capillaries,hypertensive arterial remodelling, andprominent veins located close to distalairways and arteries (‘MPV’). Cardiac cath-eterisation studies have revealed absent‘capillary blush’ phase during angiographyin infants with ACD/MPV, suggesting intra-pulmonary shunting.3 However, the contri-bution of MPV to the pathophysiology ofACD/MPV remains unknown. Preacinaranatomical communications between sys-temic (bronchial) and pulmonary vascularsystems has been extensively described4;whether they form an alternate right-to-leftvascular pathway bypassing distal lungvasculature in ACD/MPV is unclear.Postmortem injections of pulmonary arter-ies (PA), bronchial arteries (BA) and pul-monary veins (PV) were performed withcoloured inks (green, blue and black,respectively). Histology, immunohistochem-istry and three-dimensional reconstructionswere done as previously described withslight modification (see supplement).Infants’ clinical course and microscopic

pathology was typical of ACD/MPV.Injection of green and blue ink marked thevessels of PA, BA, bronchial vein (BV), PVincluding the ‘MPV’ and the bronchialmicrovessels (mv), while black ink wasvisible within the PV, BV, mv and ‘MPV’

(see online supplements 1–3). No ink fillingwas seen in alveolar capillaries or lympha-tics (see online supplements 4 and 5). MPVbridging mv and PV were frequently notedand contained all three inks (see online sup-plements 1–3) suggesting that MPV are BV

Figure 1 Upper panel: Main components of intrapulmonary vascular anastomotic pathways areshown. Three-dimensional image reconstruction (A) and histological sections (B) show directconnections between pulmonary arteries (PA) and bronchial arteries (BA) (white arrow)(BA-yellow, PA-red and blue, Bronchus (Br)-green). In an age-matched control lung, BV andpulmonary veins (PV) connections are present but appear very delicate, almost invisible (C, insertmagnifies BV-PV connection). In alveolar capillary dysplasia with misalignment of pulmonaryveins (ACD/MPV), the bronchial vessels are enlarged, especially the BV (D) appearing as dilated,thin-walled channels within the bronchovascular bundle (‘misaligned pulmonary veins’). Lowerpanel: Schematic of intrapulmonary right-to-left shunt in ACD/MPV lung is shown. The majority ofright heart blood is shunted through the arterial bronchopulmonary anastomoses (PA, BA, mv)that drains via venous bronchopulmonary anastomoses (microvessels (mv), BV, PV) leading tosignificantly decreased flow within the alveolar capillary bed.

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and may act as venous ‘shunt vessels’, as BVnormally link mv associated with airways,large vessels, pleura, and lymph nodes withPV (figure 1C).5 In addition to theexpanded venous bronchopulmonary anas-tomoses we also identified arterial broncho-pulmonary anastomoses via PA-BAconnections (figure 1, see online supple-ment 1) as part of intrapulmonaryright-to-left to vascular shunt circuit(figure 1). The prominence of these vesselsin ACD/MPV is likely due to enhanced flowthrough blood shunting from PA to sys-temic vessels that dilate mv and BV, whichbecome visible as extra vessels withinbronchoarterial bundles (‘MPV’). Thus, wepropose that rather than representing ‘mal-developed’ vessels, MPVare BV that appearmarkedly dilated due to increased bloodflow in PA-BA anastomotic vessels in ACD/MPV. In summary, we report striking intra-pulmonary vascular anastomoses in ACD/MPV that could contribute to fatal hypox-aemia due to the shunting of blood awayfrom the alveolar capillary bed.

Csaba Galambos,1,2 Sunder Sims-Lucas,3

Noorjahan Ali,2,4 Jason Gien,2,4

Megan K Dishop,1 Steven H Abman2,4

1Department of Pathology, University of ColoradoSchool of Medicine and Children’s Hospital Colorado,Aurora, Colorado, USA

2Pediatric Heart Lung Center, University of ColoradoSchool of Medicine and Children’s Hospital Colorado,Aurora, Colorado, USA3Division of Nephrology, Department of Pediatrics,Children’s Hospital of Pittsburgh of UPMC, Pittsburgh,Pennsylvania, USA4Department of Pediatrics, University of ColoradoSchool of Medicine and Children’s Hospital Colorado,Aurora, Colorado, USA

Correspondence to Dr Csaba Galambos, Departmentof Pathology and Laboratory Medicine, Children’sHospital Colorado, University School of Medicine ofColorado, 13132 East 16th Avenue, Aurora, CO 80045,USA; csaba.galambos@childrenscolorado.org

Acknowledgements The authors thank AshleyBlair, Corina Mitchell, Jana Polzer and Eric Wartchowat Children’s Hospital Colorado for technical assistance.

Contributors CG: designed experiments, performedexperiments, analysed the data, drafted and revised thepaper. He is guarantor. SS-L: performed, collected andanalysed 3D data, reviewed manuscript. NA: collectedclinical data, discussed experimental design, reviewedmanuscript. JG: collected clinical data, discussedexperimental design, reviewed manuscript. MKD:Performed experiments, reviewed manuscript. SHA:designed experiment, reviewed and revised manuscript.

Funding NIH Clinical Center (HL085703, HL68702,DK096996).

Competing interests None.

Patient consent Obtained.

Ethics approval IRB.

Provenance and peer review Not commissioned;externally peer reviewed.

▸ Additional material is published online only. To viewplease visit the journal online (http://dx.doi.org/10.1136/thoraxjnl-2014-205851).

To cite Galambos C, Sims-Lucas S, Ali N, et al.Thorax 2015;70:84–85.

Received 6 June 2014Accepted 28 June 2014Published Online First 22 July 2014

Thorax 2015;70:84–85.doi:10.1136/thoraxjnl-2014-205851

REFERENCES1 Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar

capillary dysplasia. Am J Respir Crit Care Med2011;184:172–9.

2 Parker TA, Ivy DD, Kinsella JP, et al. Combined therapywith inhaled nitric oxide and intravenous prostacyclinin an infant with alveolar-capillary dysplasia. Am JRespir Crit Care Med 1997;155:743–6.

3 Hintz SR, Vincent JA, Pitlick PT, et al. Alveolar capillarydysplasia: diagnostic potential for cardiac catheterization.J Perinatol 1999;19:441–6.

4 Shure D. The bronchial circulation in pulmonary vascularobstruction. In: Butler J, ed. The bronchial circulation.New York, NY: Marcel Dekker, 1992:579–97.

5 Barman SA, Ardell JL, Parker JC, et al. Pulmonary andsystemic blood flow contributions to upper airways incanine lung. Am J Physiol 1988;255:H1130–5.

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