Mycophenolate mofetil and triptolide alleviating airway inflammation in asthmatic model mice partly by inhibiting bone marrow eosinophilopoiesis.
The bone marrow eosinophilopoiesis makes a major contribution to the chronic airway inflammation in asthmatic animals and patients. Some anti-asthmatic medicines alleviated the asthmatic airway inflammation by inhibiting the bone marrow eosinophilopoiesis. Immunosuppressive agents have been commonly used in patients with glucocorticoid refractory asthma and have been proved to be effective. However, the research on the effect of the immunosuppressive agents on the bone marrow eosinophilopoiesis has seldom been reported. The purpose of the study was to explore the effect of mycophenolate mofetil (MMF) and triptolide (TP) on the bone marrow eosinophilopoiesis and to further investigate the mechanisms of the immunosuppressive agents involved in the anti-asthmatic effect. Balb/c mice were sensitized and challenged by OVA to establish the asthmatic model, and respectively administered orally with sterile saline, MMF, and TP once daily for 2 weeks. Airway inflammation, and inflammatory mediators IL-5 and eotaxin in the peripheral blood and bone marrow were measured by histology and ELISA. Immunocytochemistry combined with in situ hybridization technique and Western blot analysis was performed to estimate the amount of CD34+ IL-5R mRNA+ cells and IL-5R expression in the bone marrow. The count of new produced eosinophils in the bone marrow was detected by anti-BrdU immunocytochemistry. We found that MMF and TP attenuated OVA-induced eosinophil (EOS) recruitment in bronchoalveolar lavage fluid (BALF), inflammatory mediator expression of IL-5 and eotaxin in the peripheral blood, inflammatory cells expressing eotaxin in the lung tissues and the number of new produced EOS in the bone marrow. Also, MMF abated the migration of CD34+ cells from the bone marrow to the peripheral blood, which was associated with a decreased eotaxin expression in the bone marrow and a decreased CCR3 expression on bone marrow cells. While, MMF or TP failed to decrease the amount of CD34+ IL-5R mRNA+ cells (EOS progenitors), and IL-5R expression in the bone marrow of asthmatic model mice. These results demonstrated that MMF and TP reduce the eosinophilopoiesis of the bone marrow; this is associated with a decrease of IL-5 produced by T cells, which contribute to alleviate the allergic airway inflammation in asthma. In addition, MMF decreased the CD34+ cells migration from the bone marrow to the peripheral blood by the reduction of the level of eotaxin in the bone marrow and the expression of CCR3 on the bone marrow cells.
Mao
Hui
H
Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, PR China.
Chen
Xue Rong
XR
Yi
Qun
Q
Li
Su Yun
SY
Wang
Zeng Li
ZL
Li
Fu-Yu
FY
D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001853:Bone Marrow / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D004804:Eosinophils / Q000187:drug effects*; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015848:Interleukin-5 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010616:Phenanthrenes / Q000494:pharmacology / Q000627:therapeutic use*; D054397:Receptors, CCR3 / Q000032:analysis
C515351:Ccr3 protein, mouse; D004224:Diterpenes; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D010616:Phenanthrenes; D054397:Receptors, CCR3; C001899:triptolide; D009173:Mycophenolic Acid