Targeted Type 2 Alveolar Cell Depletion. A Dynamic Functional Model for Lung Injury Repair

Abstract

Type 2 alveolar epithelial cells (AEC2) are regarded as the progenitor population of the alveolus responsible for injury repair and homeostatic maintenance. Depletion of this population is hypothesized to underlie various lung pathologies. Current models of lung injury rely on either uncontrolled, nonspecific destruction of alveolar epithelia or on targeted, nontitratable levels of fixed AEC2 ablation. We hypothesized that discrete levels of AEC2 ablation would trigger stereotypical and informative patterns of repair. To this end, we created a transgenic mouse model in which the surfactant protein-C promoter drives expression of a mutant SR39TK herpes simplex virus-1 thymidine kinase specifically in AEC2. Because of the sensitivity of SR39TK, low doses of ganciclovir can be administered to these animals to induce dose-dependent AEC2 depletion ranging from mild (50%) to lethal (82%) levels. We demonstrate that specific levels of AEC2 depletion cause altered expression patterns of apoptosis and repair proteins in surviving AEC2 as well as distinct changes in distal lung morphology, pulmonary function, collagen deposition, and expression of remodeling proteins in whole lung that persist for up to 60 days. We believe SPCTK mice demonstrate the utility of cell-specific expression of the SR39TK transgene for exerting fine control of target cell depletion. Our data demonstrate, for the first time, that specific levels of type 2 alveolar epithelial cell depletion produce characteristic injury repair outcomes. Most importantly, use of these mice will contribute to a better understanding of the role of AEC2 in the initiation of, and response to, lung injury.

Expression of surfactant protein-A in exhaled breath condensate of patients with chronic obstructive pulmonary disease

“…The decrease in the total number of type II pneumocytes may be due to the extensive tissue damage in COPD (12), and has been reported in previous studies following lung injury (29,30). Type II pneumocytes proliferate during lung injury and chronic inflammatory states, including COPD, in order to produce type Ⅰ neumocytes and specific products, including SP-A), which are involved in lung defense (31).…”

A SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis

“…During the inflammatory phase of the model, there is AT2 cell apoptosis, which has been associated with the development of fibrosis in AT2 cell ablation models (72). However the 20%-30% decline in AT2 cell number we observed in this model at 4 weeks after tamoxifen treatment was a degree of apoptosis found to be insufficient to induce spontaneous fibrosis in multiple AT2 cell ablation models (73,74). Alternatively, our data show that the Sftpc C121G AT2 cell is a source of the potent fibrotic mediator TGF-β1 ( Figure 8G), although the true contribution of TGF-β1 to the development of fibrosis in this model would require TGF-β1 depletion.…”

Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis

“…The AT2 cell has been affirmed as a key progenitor (stem) cell in the distal lung contributing to a niche that mediates normal alveolar maintenance and repair (51). In preclinical model systems, selective depletion of AT2 cell mass through transgenic, spatially restricted expression of the diphtheria toxin (dT) receptor in AT2 cells followed by exogenous dT administration results in either spontaneous lung fibrosis (52,53) or enhanced susceptibility to exogenous bleomycin injury (51). Our results contribute to this growing collection of evidence for the critical role of disrupted AT2 cell homeostasis (in either function or numbers) as a proximal component in the pathogenesis of fibrotic lung remodeling.…”