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Retinoic Acid–Induced Alveolar Regeneration

Critical Differences in Strain Sensitivity

¹ M.R.C. Centre for Developmental Neurobiology, King's College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Siân V. Stinchcombe, MA, BM, BCh, M.R.C. Centre for Developmental Neurobiology, 4th Floor, New, Hunt's House, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK. E-mail: sian.stinchcombe{at}kcl.ac.uk

In emphysema, the lung cannot spontaneously regenerate lost alveolar tissue. Treatment with retinoic acid (RA) in rodent models of emphysema induces alveolar regeneration. However, some animal studies have failed to show regeneration when using different species and strains. We have previously shown that dexamethasone (Dex) treatment of newborn TO outbred strain mice permanently disrupts alveolar development. Later RA treatment restores alveolar architecture to normal. To determine whether this model of alveolar regeneration is strain specific, our protocol was repeated with two new outbred mouse strains. ICR and NIHS mice received Dex from Postnatal Days 4 to P15 (P4– P15). From P46 to P57, mice received RA (2 mg/kg) or vehicle. An additional ICR group received 5x RA (10 mg/kg) from P46 to P57. Control groups received vehicle at both treatment points. All mice were killed at P90 and lung morphology analyzed. Dex-treated ICR and NIHS mice showed increased mean alveolar chord length (Lm) and reduced alveolar surface area (SA) and SA/lung volume (SA/LV) compared with controls. RA-treated NIHS mice showed return of Lm, SA, and SA/LV toward control values, indicating alveolar regeneration. ICR RA group mice did not regenerate, but 5x RA mice showed Lm, SA, and SA/LV values consistent with alveolar regeneration. In conclusion, the Dex-treated mouse model of emphysema is robust and repeatable in different strains. RA-induced alveolar regeneration is not a strain-specific phenomenon. RA dose threshold for inducing alveolar regeneration is higher in ICR mice, suggesting a difference in retinoid pharmacokinetics between strains. These results provide a possible explanation for previous failed studies of RA-induced alveolar regeneration.

Key Words: alveolar regeneration • dexamethasone • mouse strains • pharmacokinetics • retinoic acid

CLINICAL RELEVANCE Retinoic acid–induced alveolar regeneration is not strain or sex dependent, but dose threshold can vary significantly between strains. This could explain previous failed regeneration studies and so broaden basic research approaches to future therapeutic translation.

 

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