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Review
. 2017 Mar 1;312(3):L371-L391.
doi: 10.1152/ajplung.00486.2016. Epub 2017 Jan 6.

Plasma membrane wounding and repair in pulmonary diseases

Xiaofei Cong  1 , Rolf D Hubmayr  2 , Changgong Li  3 , Xiaoli Zhao  4
Affiliations
Review

Plasma membrane wounding and repair in pulmonary diseases

Xiaofei Cong et al. Am J Physiol Lung Cell Mol Physiol. .

Abstract

Various pathophysiological conditions such as surfactant dysfunction, mechanical ventilation, inflammation, pathogen products, environmental exposures, and gastric acid aspiration stress lung cells, and the compromise of plasma membranes occurs as a result. The mechanisms necessary for cells to repair plasma membrane defects have been extensively investigated in the last two decades, and some of these key repair mechanisms are also shown to occur following lung cell injury. Because it was theorized that lung wounding and repair are involved in the pathogenesis of acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF), in this review, we summarized the experimental evidence of lung cell injury in these two devastating syndromes and discuss relevant genetic, physical, and biological injury mechanisms, as well as mechanisms used by lung cells for cell survival and membrane repair. Finally, we discuss relevant signaling pathways that may be activated by chronic or repeated lung cell injury as an extension of our cell injury and repair focus in this review. We hope that a holistic view of injurious stimuli relevant for ARDS and IPF could lead to updated experimental models. In addition, parallel discussion of membrane repair mechanisms in lung cells and injury-activated signaling pathways would encourage research to bridge gaps in current knowledge. Indeed, deep understanding of lung cell wounding and repair, and discovery of relevant repair moieties for lung cells, should inspire the development of new therapies that are likely preventive and broadly effective for targeting injurious pulmonary diseases.

Keywords: acute respiratory distress syndrome; epithelium mesenchymal cross talk; lung cells; pulmonary fibrosis.

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Figures

Fig. 1.
Fig. 1.
Interdependence of biophysical injury stimuli. Internal and external pathogenic factors, including surfactant dysregulation, regional distention, proinflammatory cytokines, bacterial toxins, viral infection, gastric acid aspiration, and cigarette smoking, collectively and interdependently injure the epithelial-endothelial barrier and further induce the pathogenesis of acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF). ROS, reactive oxygen species; RNS, reactive nitrogen species; ER, endoplasmic reticulum. Unless an arrow pointing down is present, the contents of each box are increased by its predecessor.
Fig. 2.
Fig. 2.
Normal repair mechanisms for lung cells. Lateral flow of lipid bilayer is sufficient to reseal a small membrane wound with diameter <1 µm. Membrane defects are repaired by deformation-induced lipid trafficking (DILT) and lipid vesicles from lysosome. Ca2+-dependent exosomal shedding of pore-forming toxins (PFT) pores are removed by endosomal sorting complex for transport (ESCRT) machinery. With facilitation from acid sphingomyelinase (ASM), tripartite motif-containing protein (TRIM) 72 is transported to caveolin (Cav) 1 on the membrane wound site. TRIM72 mediates caveolar endocytosis through its physical interaction with Cav1 in a Src-dependent fashion. TRIM72 polymerizes through its cysteine residues, and nonmuscle myosin type IIA (NMIIA) serves as motor to translocate TRIM72 during membrane repair. Cell membrane repairs are either enhanced or impaired by actin depolymerization. Increasing extracellular ATP inhibits translocation of lysosomal-associated membrane protein 1 (LAMP1) to membrane wound site by deactivation of ATP receptor, purinergic receptor P2Y (P2Y2R), and affects the activity of neighbor cells. Ca2+-mediated repair patch exocytosis is essential to remove the lung cell membrane defects with coordination of LAMP1, TRIM72, and de novo lipid synthesis. ASM, acid sphingomyelinase; DILT, deformation-induced lipid trafficking; CSK, subcortical cytoskeleton; PM, plasma membrane; T72, TRIM72.
Fig. 3.
Fig. 3.
Activation of aberrant tissue repair pathways following injury. On injured epithelial cell membrane, latency-associated peptide (LAP) binds to integrins αvβ6 to expose and activate the transforming growth factor (TGF)-β. Increased activated TGF-β binds to TGF-β receptor (TGFβRI and TGFβRII). Smad was phosphorylated and moved to nucleus to promote fibrotic gene expression. For Wnt signaling, injured alveolar epithelial cells secrete Wnt ligands. Wnt binds to cell surface receptor Frizzled to expose β-catenin. β-Catenin moves to nucleus and promotes the paracrine of Wnt and WISP1-mediated epithelial-mesenchymal transition (EMT) and collagen production. Epithelial injury promotes the secretion of sonic hedgehog (SHH) from injured epithelial cells. SHH releases glioma-associated oncogene homolog (GLI) by inhibiting transmembrane protein smoothened (SMO). GLI moves to nucleus to promote fibroblast proliferation, migration, and extracellular matrix (ECM) deposition. Notch signaling promotes EMT in epithelial cells and activation of fibroblasts via the intracellular domain of the notch protein (NICD). ER stress induces the expression of binding immunoglobulin protein (BiP). BiP binds and activates protein kinase R-like endoplasmic reticulum kinase (PERK), iron-responsive element 1 (IRE1), and activating transcription factor-6 (AFT6), which eventually lead to cell apoptosis.
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