Keratin-14 expression in pneumocytes as a marker of lung regeneration/repair during diffuse alveolar damage

Diffuse alveolar damage (DAD) is the chief pathological basis of life- threatening acute pulmonary conditions like the acute respiratory distress syndrome (ARDS). It may be considered as a model of lung regeneration and wound-repair, because the natural history of ARDS may include the resolution of diffuse alveolar damage (DAD) and a complete function recovery. Recent murine models of ARDS due to H1N1 infection suggested p63+/Krt5+ basal cells as tissue precursors for both airways and alveoli, but no human confirmation have been provided to date. Objectives: To investigate in human biopsy/autopsy samples of ARDS if p63+/Krt5+ cells have a pivotal role in lung regeneration following DAD. Secondarily, we challenged other possible markers of human lung regenerative process activation. Methods: We immunohistochemically analyzed a series of stem-cell related markers in 15 lung specimens of patients with ARDS/diffuse alveolar damage (DAD), comparing them with normal lung samples. Measurements and Main Results: Bronchiolar proliferation was not observed in regenerating parenchyma, where hyperplastic type-II pneumocytes did not express basal-cell markers Krt5 and ∆N-p63 (only scattered pneumocytes exhibited TA-p63 immunoreactivity revealed by a pan-p63 antibody). A striking finding in our study was a diffuse high percentage of Krt14+ pneumocytes in all DAD cases, at variance with normal controls where Krt14 expression was entirely negative. Variable Krt14 expression was evidenced in bronchiolar epithelium. A high proliferating index was observed in Krt14-expressing pneumocytes on double-stain Ki67/Krt14 preparations. No correlation was found between Krt14+ cells and clinical outcome (p>1.00). Conclusions: Our study suggests that basal cells are not involved in alveolar epithelial regeneration/repair and that Krt14 might be considered as a marker of alveolar regeneration/repair.