Aberrant lung remodeling in a mouse model of surfactant dysregulation induced by modulation of the Abca3 gene

Abstract

The lipid transporter, ATP binding cassette class A3 (ABCA3), plays a critical role in the biogenesis of alveolar type 2 (AT2) cell lamellar bodies (LBs). A relatively large number of mutations in the ABCA3 gene have been identified in association with diffuse parenchymal lung disease (DPLD), the most common of which is a missense mutation (valine substitution for lysine at residue 292 (ABCA3 E292V )) that leads to functional impairment of the transporter in vitro. The consequences of ABCA3 E292V gene expression in vivo are unknown. To address this question, we developed mouse models expressing ABCA3 E292V knocked-in to the endogenous mouse locus. The parental (F1) mouse line (mAbca3 E292V ) that retained an intronic pgk-Neo selection cassette (inserted in reverse orientation) (mAbca3 E292V -rNeo) demonstrated an allele dependent extracellular surfactant phospholipid (PL) deficiency. We hypothesize that this PL deficiency leads to aberrant parenchymal remodeling contributing to the pathophysiology of the DPLD phenotype. Compared to wild type littermates, baseline studies of mice homozygous for the pgk-Neo insert (mAbca3 E292V -rNeo +/+ ) revealed nearly 50% reduction in bronchoalveolar lavage (BAL) PL content that was accompanied by quantitative reduction in AT2 LB size with a compensatory increase in LB number. The phenotypic alteration in surfactant lipid homeostasis resulted in an early macrophage predominant alveolitis which peaked at 8 weeks of age. This was followed by age-dependent development of histological DPLD characterized initially by peribronchial inflammatory cell infiltration and culminating in both an emphysema-like phenotype (which included stereologically quantifiable reductions in both alveolar septal surface area and volume of septal wall tissue) plus foci of trichrome-positive collagen deposition together with substantial proliferation of hyperplastic AT2 cells. In addition to spontaneous lung remodeling, mABCA3 E292V -rNeo mice were rendered more vulnerable to exogenous injury. Three weeks ✩ This paper belongs to the special issue surfactants and surface activity. HHS Public Access

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

“…Mouse models. The SP-C I73T founder line (SP-C I73T-Neo ) was produced using BAC recombineering strategies to selectively knock in coding sequences for expression of an NH 2 -terminal HA-tagged murine SP-C I73T into the endogenous mouse Sftpc locus based on a targeting strategy we previously used for generation of an ABCA3 E292V line (68). Depicted in Figure 1A, the targeted allele contained an HA tag in exon 1 (the NH 2 terminus), an Ile-for-Thr substitution in exon 3a, and a FRT-PGK-gb2-Neo/km-FRT cassette (herein termed PGK-Neo) in intron 1.…”

Alveolar lipids in pulmonary disease. A review

“…BAL cells, mostly AMs, were increased and there were numerous tissue morphological changes, including peribronchial immune infiltrates and a combination of fibrotic and emphysematous regions. Bleomycin instillation, a common model of experimental fibrosis, generated worse fibrosis and higher morbidity in mutant than in WT mice [129]. Mutations in surfactant protein C (SP-C) also result in IPF development.…”

Senescence in Pulmonary Fibrosis: Between Aging and Exposure

“…Each of these cell types participate to the correct function of the lung and it is therefore central to consider how chemical exposure differentially affects each cell type to better comprehend the pathogenesis of disease. For instance, mutations of the surfactant protein (SP)-A and -C, or ATP binding cassette subfamily A member 3 (ABCA3) represent well-described examples of alveolar epithelial type 2 distress resulting in chronic lung disease and fibrosis (98,99). A number of genetic constructs successfully leveraged these mutations to produce lung fibrosis and accelerated senescence triggered by a stressed epithelium (49, 100).…”