Fibrosis characterizes many chronic diseases that result in end-stage organ failure, causing major morbidity and mortality. Fibrosis in many of these diseases appears to result from aberrant or over-exuberant wound-healing responses to chronic injury, producing excessive accumulation of fibroblasts and extracellular matrix that disrupt normal tissue homeostasis. The potent bioactive lipid lysophosphatidic acid (LPA), signaling through one of its receptors LPA₁, mediates numerous fundamental cell behaviors involved in wound healing responses, including cell contraction, migration, survival, proliferation, and gene expression. Recent studies indicate that the LPA-LPA₁ pathway regulates many of the aberrant wound-healing responses that have been implicated in fibrotic diseases. This pathway has been shown to exert pro-fibrotic effects on multiple cell types: LPA-LPA₁ signaling promotes epithelial cell apoptosis and fibroblast migration, proliferation and resistance to apoptosis, and impairs endothelial cell barrier function. Consistent with its broad pro-fibrotic activities, inhibition of the LPA-LPA₁ pathway has recently been demonstrated to have profound anti-fibrotic effects. Targeting LPA-LPA₁ signaling has been demonstrated to be an effective therapeutic strategy in mouse models of fibrotic diseases affecting multiple different organs, including the lung, kidney, skin and peritoneum. The breadth of these effects suggest that LPA and LPA₁ represent a core pathway in fibrosis, and make these molecules attractive targets for the development of new therapies with the potential to be effective for multiple human fibrotic diseases.

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Chronic inflammation-associated kidney fibrosis leads to progressive kidney dysfunction. Cell sources of matrix-producing cells in diseased kidneys include activated resident stromal cells (e.g., fibroblasts and pericytes), cells derived from epithelial-mesenchymal transition/endothelial-mesenchymal transition, and infiltrating bone-marrow-derived cells (e.g., fibrocytes, T cells, and monocytes/macrophages). Recent studies show that bone-marrow-derived cells are recruited to diseased kidneys, interact with renal resident cells, and produce chemokines/cytokines, growth factors, and collagens, thereby promoting and escalating chronic inflammatory processes and eventually leading to kidney fibrosis.

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Sphingosine-1-phosphate (S1P) is a pleiotropic lysophospholipid mediator that acts on 5 members of the G protein-coupled S1P receptor family to induce diverse biological responses. S1P1, S1P2 and S1P3, which are widely expressed receptor subtypes, exert distinct regulatory effects on cytoarchitecture, cell migration, proliferation and gene expression, through differential coupling to heterotrimeric G proteins and downstream signaling, including activation of Rac and Rho small GTPases. Recent studies indicate the involvement of the S1P signaling system in inflammation and fibrosis. Investigations into genetically engineered mice have provided evidence that S1P2 and S1P3 receptors, together with sphingosine kinase 1 (SphK1), which is a major S1P synthesizing enzyme, participate in fibrogenic processes, through mechanisms involving activation of the Rho-dependent pathway and cross-talk with TGFβ signaling. This review will focus on the basics of the S1P signaling system, which include S1P receptor subtype-specific signaling and biological activities, production and degradation of S1P, and currently available in vivo data, including our own data, regarding how S1P signaling is involved in cardiac fibrosis, a pathological feature of cardiac remodeling that leads to chronic heart failure, which is one of leading causes of death in developed countries.

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by fibroblast proliferation and excess deposition of extracellular matrix proteins in the lungs. As anti-inflammatory therapies such as steroids or immunosuppressive agents do not improve disease progression, targets to block fibrogenesis per se are needed. Mice lacking cytosolic phospholipase A₂, a key enzyme triggering the production of arachidonic acid metabolites such as eicosanoids including prostanoids and leukotrienes, did not develop bleomycin-induced pulmonary fibrosis, indicating that arachidonic acid metabolites play an important role in the pathogenesis of pulmonary fibrosis. Previous reports indicated that leukotrienes have fibrogenic effects, and prostaglandins (PGs) E₂ and I₂ have antifibrogenic effects. We have reported that, using mice lacking each prostaglandin receptor, PGF_2α and its receptor FP signaling facilitated bleomycin-induced pulmonary fibrosis through increased fibroblast proliferation and collagen deposition, independently of transforming growth factor (TGF)-β signaling. Furthermore, to evaluate the clinical significance of PGF_2α in IPF, using the liquid chromatography-tandem mass spectrometry, the levels of 15-keto-dihydro PGF_2α as well as PGF_2α increased in the bronchoalveolar lavage fluid of patients with IPF to a greater extent than in patients with sarcoidosis. Thus, we have suggested PGF_2α-FP signaling as a therapeutic target for IPF. Eicosanoids may be promising targets for novel treatments and management of IPF, in addition to TGF-β.

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Cardiac regenerative medicine is emerging as a new approach to treat severe cardiovascular diseases that are resistant to conventional therapies. To achieve fair engraftment and efficient outcome, the method of cell transplantation is important, as the efficacy of engraftment after simple needle injection is relatively poor. Using biomaterials (e.g. collagen, fibrin, gelatin or matrigel) as a scaffold of the transplanted cells is an effective method, and various attempts to control cell distribution for the creation of tissue-like structure have been made. In this regard, scaffold-free cell sheet technology using temperature-responsive culture surface is another promising method because it bears potential for generating three-dimensional tissue-like structure in vitro. Furthermore, the cell sheet system enables us to elucidate the cellular mechanisms for cardiac regeneration. Combination of cell therapy and sustained release of growth factors, such as basic fibroblast growth factor, is another valuable approach for cell engraftment and augmentation of the potential of cell transplantation. Herein, we review various engraftment strategies of the transplanted cells to achieve more efficient outcome in cardiac cell therapy. We expect that these advanced modalities with bioengineering technology would largely contribute to cardiac regenerative medicine.

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Rheumatoid arthritis (RA) is immunologically characterized by generation of anti-citrullinated peptide antibodies (ACPAs). To promote understanding of ACPAs, we here identified novel ACPA antigens by proteomics using in vitro citrullination and investigated effects of citrullination on one of the ACPA antigens. Specifically, we citrullinated protein extracts from Jurkat cells in vitro and separated the citrullinated protein extracts as well as non-treated ones by 2-dimensional electrophoresis (2DE). By western blotting, we detected protein spots that reacted to RA serum samples only when they were citrullinated and identified them by mass spectrometry. On two of the identified proteins, adenosine deaminase (ADA) 1 and proliferation associated protein 2G4 (PA2G4), we confirmed the citrulline-dependent recognition by ACPAs using enzyme-linked immunosorbent assay (ELISA). Finally, we compared the activity of citrullinated ADA1 and non-treated one. As a result, we detected 8 candidate antigens for ACPAs, and identified 7 of them. In ELISA, 6 (24%) out of the tested 25 RA serum samples reacted to citrullinated ADA1, but none (0%) to non-treated ADA1 (p=0.022). Similarly, 9 (36.0%) out of the same RA samples reacted to citrullinated PA2G4, but only 1 (4.0%) to non-treated PA2G4 (p=0.01). In addition, we found that citrullination enhanced activity of ADA. In conclusion, we demonstrated novel autoantigens for ACPAs including ADA1 and PA2G4 and enhancement of the ADA activity by citrullination. The enhanced ADA activity may decrease anti-inflammatory adenosine and thus may hamper the pharmaceutical increase of adenosine by methotrexate in RA.

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