Vascular endothelial growth factor (VEGF) is not only an important factor for angiogenesis but also lung development and homeostasis. VEGF-A binds three tyrosine kinase (TK) receptors VEGFR1–3. Idiopathic pulmonary fibrosis (IPF) is one of the poor prognoses of lung diseases. The relationship of VEGF and IPF remains to be clarified. Treatment with nintedanib used for the treatment of IPF reduced fibroblast proliferation, inhibited TK receptors, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and VEGFR. Because the effect of that treatment is still not satisfactory, the emergence of new therapeutic agents is needed. This review describes the enhancement of pulmonary fibrosis by VEGFR1-TK signal and suggests that the blocking of the VEGFR1-TK signal may be useful for the treatment of pulmonary fibrosis.

Accumulation of myeloid-derived suppressor cells (MDSCs) to tumors is related to cancer prognosis. We investigated the contribution of host stromal microsomal prostaglandin E synthase-1 (mPGES-1) to the accumulation of MDSCs in metastasized lungs of prostate cancer in mice. Eight-week-old male C57Bl/6 wild type (WT) mice and mPGES-1 knock out mice (mPGES-1KO) were injected with RM9 murine prostate cancer cell line (5 × 10⁶ cells/mL). Lung metastasis was evaluated by the number of colonies, the weight of the lung, and the number of MDSCs (CD11b⁺Gr1⁺ cells) in the lung. Intravenous injections of RM9, a murine prostate cancer cell line to WT mice revealed that lung metastasis and accumulation of MDCSs were suppressed with treatments with a Gr1 antibody, a COX-2 inhibitor, and an mPGES-1 inhibitor. Lung metastasis and accumulation of CD11b⁺Gr1⁺MDSCs were suppressed in mPGES-1KO mice. The mRNA level of stromal cell-derived factor-1 (SDF-1) in the lung and the number of accumulated SDF-1-expressing CD11b⁺Gr1⁺ MDSCs were elevated at an early stage in lung metastasis of C-X-C chemokine receptor type 4 (CXCR4)-expressing RM9 in an mPGES-1-dependent manner. The number of CXCR4-expressing CD11b⁺Gr1⁺MDSCs in WT mice was higher than that in mPGES-1KO mice. RM9 lung metastasis and accumulation of CD11b⁺Gr1⁺MDSCs were suppressed by CXCR4 antibody in WT mice but not in mPGES-1KO. WT mice transplanted with mPGES-1 KO bone marrow (BM) showed a significant reduction in lung metastasis and accumulation of CD11b⁺Gr1⁺MDSCs. These results suggest that mPGES-1 enhances tumor metastasis by inducing accumulation of BM-derived MDSCs. Selective mPGES-1 inhibitors might, therefore, represent valuable therapeutic tools for the suppression of tumor metastasis.

Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin–angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensinIIsubtype receptor 1a (AT1a) in the formation of liver metastasis inCRC. A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer (CMT‐93) intoAT1a knockout mice (AT1aKO) and wild‐type (C57BL/6) mice (WT). Compared withWTmice, the liver weight and liver metastatic rate were significantly lower inAT1aKO. ThemRNAlevels ofCD31, transforming growth factor‐ β1 (TGF‐β1), and F4/80 were suppressed inAT1aKOcompared withWT. Double immunofluorescence analysis showed that the number of accumulated F4/80⁺cells expressingTGF‐β1 in metastatic areas was higher inWTthan inAT1aKO. TheAT1aKObone marrow (BM) (AT1aKO‐BM)→WTshowed suppressed formation of liver metastasis compared withWT‐BM→WT. However, the formation of metastasis was further suppressed inWT‐BM→AT1aKOcompared withAT1aKO‐BM→WT. In addition, accumulated F4/80⁺cells in the liver metastasis were notBM‐derived F4/80⁺cells, but mainly resident hepatic F4/80⁺cells, and these resident hepatic F4/80⁺cells were positive forTGF‐β1. AngiotensinIIenhancedTGF‐β1 expression in Kupffer cells. Treatment ofWTwith clodronate liposomes suppressed liver metastasis by diminishingTGF‐β1⁺F4/80⁺cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent onAT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction ofTGF‐β1 throughAT1a signaling.

Destruction of liver sinusoidal endothelial cells (LSECs) is an initial event in sinusoidal obstruction syndrome (SOS) that leads to accumulation of platelets in the liver. Herein, we explored the role of platelets during progression of experimental SOS induced by monocrotaline (MCT) in mice. Depletion of platelets using an anti-CD41 antibody or anti-thrombocyte serum exacerbated MCT-induced liver injury in C57BL/6 mice, as indicated by an increase in the alanine transaminase (ALT) level, which was associated with hemorrhagic necrosis. Thrombocytosis induced by thrombopoietin (TPO) or the TPO receptor agonist romiplostim (ROM) attenuated MCT-induced liver injury, as evidenced by lower levels of ALT and mRNA encoding matrix metalloproteinase (MMP) 9, and higher levels of mRNA encoding vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3. The level of activated hepatic platelets was higher in TPO- and ROM-treated mice than in saline-treated mice. Co-culture with a high number of platelets increased the viability of LSECs and their mRNA levels of CD31, VEGFR2, and VEGFR3, and decreased their mRNA level of MMP9. The level of VEGF-A was increased in the culture medium of LSECs co-cultured with platelets. These results indicate that platelets attenuate MCT-induced liver injury by minimizing damage to LSECs.