LIPUS as a potential strategy for anti-inflammation and repair: A review of the mechanisms

Abstract

Hundreds of millions of people worldwide endure continuous suffering and significant economic burdens due to inflammatory diseases. Various acute and chronic inflammatory diseases and the natural aging of the human body are common causes of organ damage. Therefore, how to reasonably regulate inflammation, tissue repair and regeneration after organ damage has been of great concern, especially the pathological repair caused by inflammation will lead to the destruction of the original structure and function of tissues and organs. Low-intensity pulsed ultrasound (LIPUS) is a promising non-invasive physical therapy that can produce different biological effects on organs, tissues and cells. Certain clinical trials have demonstrated the outstanding capacity of LIPUS in anti-inflammation and repair. Many in vivo and in vitro basic studies have also reported the molecular effect mechanisms by which LIPUS exerts capacity of anti-inflammation and repair. This review focuses on the molecular mechanism of LIPUS anti-inflammation and repair and emphasizes the crucial role of LIPUS in various diseases. In addition, we compile clinical trials to provide readers with a more thorough understanding of the current potential of LIPUS in inflammation control and organ function restoration.

Keywords: inflammation; low-intensity pulsed ultrasound (LIPUS); molecular mechanism; repair; signaling pathway.

Figure 1

Molecular and cellular processes involved in the LIPUS bioeffects. By Figdraw. Abbreviations: BDNF: brain-derived neurotrophic factor; CAP: cholinergic anti-inflammatory pathway; EVs: extracellular vesicles; FAK: focal adhesion kinase; HIF: hypoxia-inducible factor; NF-κB: nuclear factor-κB.

Figure 2

The application of LIPUS in anti-inflammation and repair at the biological and molecular level. LIPUS up-regulated phosphorylated FAK in synovial cells, leading to decreased ERK, c-JNK, and p38 phosphorylation. LIPUS modulated apoptosis and survival of osteoarticular synoviocytes through the integrin/FAK/MAPK signaling pathway. LIPUS activates SCs through the TrkB/Akt/CREB axis in peripheral nerves, enhancing SCs proliferation, migration, and nerve growth factor expression. In an adriamycin-induced chronic renal injury model, LIPUS treatment significantly ameliorated renal injury by blocking signaling between TGF-β1 and its downstream molecules, Smad2 and Smad3 to reduce fibrosis and inflammation. LIPUS partially mitigated hypoxia-induced cardiac fibroblast phenotypic changes through the TRAAK-mediated HIF-1α/DNMT3a signaling pathway. In LPS-induced NP cells, LIPUS inhibited the NF-κB signaling pathway by suppressing p-P65 protein expression and P65 translocation to the nucleus, i.e., inhibiting the NF-κB signaling pathway, inflammation, and catabolism in LPS-induced human degenerative medulla oblongata cells. By Figdraw. Abbreviation: CREB: cyclic-AMP response binding protein; DNMT3a: DNA methyltransferase3α; ERK: extracellular regulated protein kinases; HIF: hypoxia-inducible factor; JNK: c-Jun N-terminal kinase; LIPUS: low intensity pulse ultrasound; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor-κB; NP: nucleus pulposus; SCs: Schwann cells; TrkB: tyrosine Kinase receptor B; TGF-β: transforming growth factor-β; TRAAK: TWIK-related arachidonic acid-activated K⁺ channel.

Figure 3

The capacity of LIPUS in anti-inflammation and repair via multiple signaling pathways. NE released from the splenic nerve treated by LIPUS stimulated CD4⁺ T cells to release ACh, making leukocytes releasing cytokines. This could modulate inflammatory cells migration and inflammatory factors release. EVs produced by LIPUS-treated BMSCs contained higher levels of miR-328-5p and miR-487b-3p, targeting genes in the MAPK signaling pathway. LIPUS treatment increased miR-16 and miR-21 levels in BMDC exosomes, targeting and inhibiting the NF-κB signaling pathway. The WNT/FZD5/β-catenin axis and PPARγ signaling pathway were encential for LIPUS to promote M2 polarization. By Figdraw. Abbreviation: Ach: acetylcholine; BMSCs, bone marrow-derived mesenchymal stem cells; BMDC: bone dendritic cell; CAP: cholinergic anti-inflammatory pathway; EVs: extracellular vesicles; LIPUS: low intensity pulse ultrasound; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor-κB; NE: Norepinephrine; PPARγ: peroxisome proliferator activated receptor γ.

Figure 4

The main mechanism of LIPUS in tissue injury: anti-inflammation and repair. LIPUS promotes the osteogenic differentiation of BMSCs and enhances angiogenesis to facilitate fracture healing. (B) LIPUS improves chronic prostatitis by regulating the balance of microbiota. (C) LIPUS reduces inflammation in chondrocytes and synovial cells, while promoting the formation of the extracellular matrix. (D) LIPUS promotes the increase of BDNF to protect the brain or peripheral nerve injury and reduce the infiltration of M1-like inflammatory cells; it alleviates ER stress to protect neurons. (E) LIPUS promotes the increase of BDNF to protect the brain or peripheral nerve injury and reduce the infiltration of M1-like inflammatory cells; it alleviates ER stress to protect neurons. (F) LIPUS reduces the production of inflammatory factors and fibroblasts to alleviate inflammation and fibrosis. (G) LIPUS alleviates degenerative human nucleus pulposus by promoting extracellular matrix formation and reducing inflammatory factors. (H) LIPUS alleviates renal injury-induced fibrosis by reducing TGF. (I) LIPUS promotes muscle injury repair by reducing M1 cells and increasing myotubes and myoblasts. Figure was drawn by BioRender.com. Abbreviation: BDNF: brain-derived neurotrophic factor; BMSC: bone marrow-derived mesenchymal stem cell; HIF: hypoxia-inducible factor; HPDLC: human periodontal ligament cell; JNK: c-Jun N-terminal kinase; LIPUS: low intensity pulse ultrasound; NF-κB: nuclear factor-κB; TGF-β: transforming growth factor-β.