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Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome

ABSTRACT: Proteasomes are a critical component of quality control that regulates turnover of short-lived, unfolded, and misfolded proteins. Proteasome activity has been therapeutically targeted and considered as a treatment option for several chronic lung disorders including pulmonary fibrosis. Though pharmacologic inhibition of proteasome activity effectively prevents the transformation of fibroblasts to myofibroblasts, the effect on alveolar type 2 (AT2) epithelial cells is not clear. To address this knowledge gap, we generated a genetic model in which a proteasome subunit, RPT3, which promotes assembly of active 26S proteasome, was conditionally deleted in AT2 cells of mice. Targeted deletion of RPT3 in AT2 cells resulted in 26S proteasome dysfunction, leading to augmented cell stress and death. Acute loss of AT2 cells resulted in depletion of alveolar surfactant, disruption of the alveolar epithelial barrier and, ultimately, lethal acute respiratory distress syndrome. This study underscores the need for further investigation into the differential effect of proteasome inhibition in lung cell types.

ORGANISM(S): Mus musculus

PROVIDER: GSE123873 | GEO | 2019/08/29

REPOSITORIES: GEO

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Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.

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Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome

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