Keratin-14 Expression in Pneumocytes as a Marker of Lung Regeneration/Repair during Diffuse Alveolar Damage

Diffuse alveolar damage (DAD) is the chief \npathological basis of life- threatening acute pulmonary conditions \nlike the acute respiratory distress syndrome (ARDS). It may be \nconsidered as a model of lung regeneration and wound-repair, \nbecause the natural history of ARDS may include the resolution of \ndiffuse alveolar damage (DAD) and a complete function recovery. \nRecent murine models of ARDS due to H1N1 infection suggested \np63+/Krt5+ basal cells as tissue precursors for both airways and \nalveoli, but no human confirmation have been provided to date. \nObjectives: To investigate in human biopsy/autopsy samples of \nARDS if p63+/Krt5+ cells have a pivotal role in lung regeneration \nfollowing DAD. Secondarily, we challenged other possible markers \nof human lung regenerative process activation. Methods: We \nimmunohistochemically analyzed a series of stem-cell related \nmarkers in 15 lung specimens of patients with ARDS/diffuse \nalveolar damage (DAD), comparing them with normal lung \nsamples. Measurements and Main Results: Bronchiolar \nproliferation was not observed in regenerating parenchyma, where \nhyperplastic type-II pneumocytes did not express basal-cell \nmarkers Krt5 and ∆N-p63 (only scattered pneumocytes exhibited \nTA-p63 immunoreactivity revealed by a pan-p63 antibody). A \nstriking finding in our study was a diffuse high percentage of \nKrt14+ pneumocytes in all DAD cases, at variance with normal \ncontrols where Krt14 expression was entirely negative. Variable \nKrt14 expression was evidenced in bronchiolar epithelium. A high \nproliferating index was observed in Krt14-expressing \npneumocytes on double-stain Ki67/Krt14 preparations. No \ncorrelation was found between Krt14+ cells and clinical outcome \n(p>1.00). Conclusions: Our study suggests that basal cells are not \ninvolved in alveolar epithelial regeneration/repair and that Krt14 \nmight be considered as a marker of alveolar regeneration/repair.