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(Circulation Research. 2004;95:e35.)
© 2004 American Heart Association, Inc.

Letter to the Editor

Modeling Alveolar Capillary Dysplasia

Csaba Galambos

Division of Pediatric Pathology, Children’s Hospital of Pittsburgh, Pittsburgh, Pa, csaba.galambos{at}chp.edu

To the Editor,

I read with great interest the article by Han et al,¹ who studied lung morphology in developing endothelial NO synthase (eNOS)-deficient mice. The authors presented exciting data on defective peripheral lung vessel development, which was combined with impaired alveolar maturation. These data reflect very well the current thinking of lung development regulated by molecular cross-talk between mesenchymal and epithelial elements.² One main point suggested by the authors was the resemblance of the eNOS-deficient mouse pulmonary phenotype to a "new" human clinical syndrome, alveolar capillary dysplasia (ACD). The authors observed thin-walled channels (veins) in close proximity to the pulmonary broncho-arterial units of the eNOS-deficient mouse lung (see Figure 4g in Han et al¹), and, therefore, they proposed that the eNOS-deficient mouse be considered an animal model for ACD.

In my opinion, this proposal deserves careful rethinking. ACD, although uncommon, has been recognized for more than 2 decades.³ There is an ongoing debate regarding the exact pathomechanism, but it is clear that the main pathology primarily involves developing air-blood barriers.⁴ The characteristic pathologic findings are as follows: (1) decreased number of pulmonary capillaries per airway unit; (2) failure of fusion of individual capillaries with type I pneumocytes; and (3) central localization of capillaries in alveolar septae. Demonstration of decreased number of air-blood barriers⁵ or decreased numbers of type I pneumocytes⁵ is a much more reliable method in the assessment of ACD pathology than finding misaligned pulmonary veins, because they may or may not present in ACD and are, therefore, not considered essential in this disorder.

Given the experimental system of the authors’, which clearly requires manipulation of main pulmonary arteries and airways, it is tempting to speculate that the presence of large, thin-walled channels on Figure 4g of their article may not be veins, but dilated lymphatics. In our pediatric pathology practice, dilated lymphatic channels within the pulmonary broncho-arterial units are commonly present in lung specimens of neonates requiring mechanical ventilation. Using a novel antibody, D2–40, with high specificity and modest sensitivity to lymphatic endothelium is a possible technique that could clarify this issue.⁶

References

1. Han RN, Babaei S, Robb M, Lee T, Ridsdale R, Ackerley C, Post M, Stewart DJ. Defective lung vascular development and fatal respiratory distress in endothelial NO synthase-deficient mice: a model of alveolar capillary dysplasia? Circ Res. 2004; 94: 1115–1123.[Abstract/Free Full Text]
2. Shannon JM, Hyatt BA. Epithelial-mesenchymal interactions in the developing lung. Annu Rev Physiol. 2004; 66: 625–645.[CrossRef][Medline] [Order article via Infotrieve]
3. Janney CG, Askin FB, Kuhn C 3rd. Congenital alveolar capillary dysplasia–an unusual cause of respiratory distress in the newborn. Am J Clin Pathol. 1981; 76: 722–727.[Medline] [Order article via Infotrieve]
4. Rabah R, Poulik JM. Congenital alveolar capillary dysplasia with misalignment of pulmonary veins associated with hypoplastic left heart syndrome. Pediatr Dev Pathol. 2001; 4: 167–174.[CrossRef][Medline] [Order article via Infotrieve]
5. Galambos C, Ng YS, Ali A, Noguchi A, Lovejoy S, D’Amore PA, DeMello DE. Defective pulmonary development in the absence of heparin-binding vascular endothelial growth factor isoforms. Am J Respir Cell Mol Biol. 2002; 27: 194–203.[Abstract/Free Full Text]
6. Nodit L., Galambos C. Identification of lymphatic endothelium in pediatric vascular tumors and malformations. Mod Pathol. 2004; 17: 270. Abstract.

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