Research Progress of Pericytes in Pulmonary Fibrosis

¹ Department of Critical Care Medicine; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital of Guangzhou Medical University, 510150 Guangzhou, Guangdong, China

² State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affliated Hospital of Guangzhou Medical University, 510182 Guangzhou, Guangdong, China

^*Correspondence: tangxiaoxiao@gird.cn (Xiao Xiao Tang); wangyichun2005@163.com (Yichun Wang)

Front. Biosci. (Landmark Ed) 2024, 29(4), 141; https://doi.org/10.31083/j.fbl2904141

Submitted: 6 July 2023 | Revised: 19 February 2024 | Accepted: 6 March 2024 | Published: 8 April 2024

This is an open access article under the CC BY 4.0 license.

Abstract

Pericytes, a specific type of mesenchymal cell that surround the basement membrane of pulmonary venules and capillaries. They are crucial pathological features observed in individuals with the severe lung disease of pulmonary fibrosis (PF). The presence of pericytes leads to inflammation and fibrosis in the lung interstitium and alveolar space due to the release of various cytokines and chemokines. Pericytes also stimulate the proliferation and activation of fibroblasts, thereby promoting the progression of PF. Previous studies examining the mechanism of action of pericytes have primarily focused on cell signal transduction pathways, cell growth and death processes, and the synthesis and breakdown of extracellular matrix (ECM). Notably, the transforming growth factor- $\beta{}$ (TGF- $\beta{}$ ) and Wnt signaling pathways have been associated with the action of pericytes in driving the progression of PF. It is therefore clear that pericytes play an essential role in the development of PF, while also offering possible avenues for targeted therapeutic intervention against this condition. The current article provides a comprehensive review on how pericytes contribute to inflammatory responses, as well as their importance for understanding the mechanism of PF. In addition, this review discusses the potential use of pericyte-targeted approaches for the treatment of patients affected by this debilitating lung disease.

Keywords

pulmonary fibrosis

pericytes

myofibroblasts

transformation

Funding

SKLRD-OP-202320/Open Project of the State Key Laboratory of Respiratory Disease

2023B01J1002/Key Research and Development Project of Guangzhou Science and Technology Burea

Figures

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Fig. 1.

The mechanism underlying pericyte transformation into myofibroblasts. (a) transforming growth factor- $\beta{}$ (TGF- $\beta{}$ ) production was increased (damaged epithelial cells produce TGF- $\beta{}$ ; toll-like receptor 4 (TLR-4) and TGF- $\beta{}$ were highly expressed in pericytes upon lipopolysaccharide (LPS) induction; and Sirtuin 3 (SIRT3) highly expresses TGF- $\beta{}$ by increasing reactive oxygen species (ROS) levels), and then TGF- $\beta{}$ with receptor phosphorylation, multiple downstream adjustment factor is activated (e.g., Smad2/3 signaling, and non-Smad pathways). Phosphorylated TGF- $\beta{}$ promotes the phosphorylation of Smad2/3 and extracellular regulated protein kinase 1 (ERK1), leading to pericyte-myofibroblast transition (PMT). Phosphorylated Smad2/3 (P-Smad2/3) translocated to the nucleus, and the accumulation of P-Smad2/3 in the nucleus increases the binding to Smad-binding elements (SBE), leading to increased transcription of fibrotic genes, which in turn increases matrix proteins (including collagen type I) leading to increased extracellular matrix (ECM) deposition. Binding of FAK to the ECM leads to increased translocation of MKL-1, yes-associated protein (YAP), and transcriptional coactivators with PDZ-binding motifs (TAZ), which in turn lead to increased $\alpha{}$ -SMA ${}^{+}$ expression and myofibroblast transition, leading to idiopathic pulmonary fibrosis (IPF). (b) Notch1 and exogenous bleomycin can regulate platelet-derived growth factor receptor (PDGFR) activity, and PDGFR activation can regulate a variety of downstream signaling molecules, such as Ras, phosphatidylinositol 3-Kinase (PI3K) and phospholipase C (PLC). In addition, PDGFR also regulates Rho-related protein kinase 1 (ROCK1), which is involved in the pathogenesis of pulmonary fibrosis, while PDGF signaling can stimulate ERK1/2 activation in pericytes. (c) Macrophages can modulate the vascular endothelial growth factor (VEGF) /PI3K pathway through the gasdermin D (GSDMD)/ interleukin-1 $\beta{}$ (IL-1 $\beta{}$ ) axis, thereby altering the transition of pericytes to fibrosis. (d) damage-associated molecular patterns (DAMPs) occur when cells are damaged, bind to receptors TLR2/4 on pericytes, induce changes in MyD88 and interleukin-1 receptor associated kinase 4 (RAK4) signaling and develop pulmonary fibrosis. (e) The mTOR is a member of the phosphatidylinositol-3-OH-kinase-related family, TGF- $\beta{}$ binds to its receptor and activates Akt/mTOR signaling pathway to mediate the proliferation of ECM and PMT.

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