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Review
. 2021 Oct;65(4):347-365.
doi: 10.1165/rcmb.2020-0476TR.

Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis

Victoria A Ptasinski  1   2   3   4 , John Stegmayr  2   3   4 , Maria G Belvisi  1   5 , Darcy E Wagner  2   3   4 , Lynne A Murray  1
Affiliations
Review

Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis

Victoria A Ptasinski et al. Am J Respir Cell Mol Biol. 2021 Oct.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Current evidence suggests that IPF may be initiated by repeated epithelial injuries in the distal lung, which are followed by abnormal wound healing responses that occur because of intrinsic and extrinsic factors. Mechanisms contributing to chronic damage of the alveolar epithelium in IPF include dysregulated cellular processes such as apoptosis, senescence, abnormal activation of the developmental pathways, aging, and genetic mutations. Therefore, targeting the regenerative capacity of the lung epithelium is an attractive approach in the development of novel therapies for IPF. Endogenous lung regeneration is a complex process involving coordinated cross-talk among multiple cell types and reestablishment of a normal extracellular matrix environment. This review will describe the current knowledge of reparative epithelial progenitor cells in the alveolar region of the lung and discuss potential novel therapeutic approaches for IPF, focusing on endogenous alveolar repair.

Keywords: epithelium; lung; regeneration; stem cells.

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Figures

Figure 1.
Figure 1.
Strategies to promote therapeutic lung regeneration. Regenerative subpopulations have been found to reside in the bronchi (BESCs and subpopulations of club cells), bronchiolar epithelium (DASCs, LNEPs, and v-CCs), and alveoli (BASCs, AEPs, AEC2s, and subpopulations of AEC1s) in lung injury models as described in Table 2. Strategies to promote therapeutic lung regeneration include the exogenous administration of stem cells, including primary distal endogenous epithelial progenitor cells, multi- or pluripotent stem cells (MSCs, ESCs, iPSCs), stem cell–derived distal epithelial progenitor cells, and directly reprogrammed distal epithelial progenitor cells. Endogenous activation of distal epithelial progenitor cells to promote self-renewal, proliferation, and differentiation of the alveolar epithelium can be induced through modulation of the molecular environment (signaling pathways, extracellular matrix) or by directly targeting individual cell types. Potential future therapeutics include gene therapy (administration of oligonucleotides and gene editing); administration of peptides such as growth factors, cytokines, and proteins; inhibition of receptors and targets with antibodies; and administration of small molecules, nanoparticles, and nanobodies designed for specific targets of interest. AEC1 = alveolar epithelial type 1 cell; AEC2 = alveolar epithelial type 2 cell; AEP = alveolar epithelial progenitor cell; BASC = bronchioalveolar stem cell; BESC = bronchial epithelial stem cell; DASC = distal airway stem cell; ESC = embryonic stem cell; iPSC = induced pluripotent stem cell; LNEP = lineage-negative epithelial progenitor cell; MSC = mesenchymal stem cell; Sp-C = SFTPC; v-CC = variant club cell.
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