The Development of Integrin Alpha-8 Deficient Lungs Shows Reduced and Altered Branching and a Correction of the Phenotype During Alveolarization.

Tiziana P Cremona,Johannes C Schittny,Andrea Hartner

doi:10.3389/fphys.2020.530635

Tiziana P Cremona, Johannes C Schittny + Show 1 more

Open Access

https://doi.org/10.3389/fphys.2020.530635

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Abstract

Lung development involves epithelial–mesenchymal interactions and integrins represent one of the key elements. These extracellular matrix receptors form hetero-dimers of alpha and beta subunits. The integrin α8β1 is highly expressed in mouse tissues, including lung. It forms a cellular receptor for fibronectin, vitronectin, osteopontin, nephronectin, and tenascin-C. This study aims to investigate the role of the integrin α8-subunit (α8) during lung development. Wild type and α8-deficient lungs were explanted at embryonic days 11.5/12.5. After 24–73 h in culture α8-deficient lung explants displayed reduced growth, reduced branching, enlarged endbuds, altered branching patterns, and faster spontaneous contractions of the airways as compared to wild type. Postnatally, a stereological investigation revealed that lung volume, alveolar surface area, and the length of the free septal edge were significantly reduced in α8-deficient lungs at postnatal days P4 and P7. An increased formation of new septa in α8-deficient lungs rescued the phenotype. At day P90 α8-deficient lungs were comparable to wild type. We conclude that α8β1 takes not only part in the control of branching, but also possesses a morphogenic effect on the pattern and size of the future airways. Furthermore, we conclude that the phenotype observed at day P4 is caused by reduced branching and is rescued by a pronounced formation of the new septa throughout alveolarization. More studies are needed to understand the mechanism responsible for the formation of new septa in the absence of α8β1 in order to be of potential therapeutic benefit for patients suffering from structural lung diseases.

Highlights

Lung DevelopmentThe lungs are the main organ of respiration present in human, mice, and higher vertebrates
New branching formation was quantified for each explant at different time points and significant differences were detected between wild type (WT) and α8 deficient mice or lungs (KO)+ explants after 43 h of lung culture
No difference was observed between WT and KO− (Figure 2A)

Summary

Introduction

The lungs are the main organ of respiration present in human, mice, and higher vertebrates. They provide a large internal surface area where the inspired air and the capillary blood get in close contact to each other to allow an efficient exchange of gases. To achieve this goal, during lung development, six important and overlapping stages occur: organogenesis, pseudoglandular stage, canalicular stage, saccular stage, alveolarization, and microvascular maturation. During the pseudoglandular and canalicular stage, large parts of the pulmonary airways are formed prenatally by branching morphogenesis. Monkeys, dogs and others, the bronchial tree is formed by a repetitive dichotomous branching of the future airways whereas in rodents, branching follows a monopodial pattern (Woods and Schittny, 2016)

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