[Show abstract][Hide abstract] ABSTRACT: Abstract Context: There are few short-term mouse models of chronic obstructive pulmonary disease (COPD) mimicking the human disease. In addition, p38 is recently recognized as a target for the treatment of COPD. However, the precise mechanism how p38 contributes to the pathogenesis of COPD is still unknown. Objective: We attempted to create a new mouse model for COPD by intra-tracheal administration of a mixture of lipopolysaccharide (LPS) and cigarette smoke solution (CSS), and investigated the importance of the p38 mitogen-activated protein kinase (p38) pathway in the pathogenesis of COPD. Methods: Mice were administered LPS + CSS once a day on days 0-4 and 7-11. Thereafter, CSS alone was administered to mice once a day on days 14-18. On day 28, histopathological changes of the lung were evaluated, and bronchoalveolar lavage fluid (BALF) was subjected to western blot array for cytokines. Transgenic (TG) mice expressing a constitutive-active form of MKK6, a p38-specific activator in the lung, were subjected to our experimental protocol of COPD model. Results: LPS + CSS administration induced enlargement of alveolar air spaces and destruction of lung parenchyma. BALF analyses of the LPS + CSS group revealed an increase in expression levels of several cytokines involved in the pathogenesis of human COPD. These results suggest that our experimental protocol can induce COPD in mice. Likewise, histopathological findings of the lung and induction of cytokines in BALF from MKK6 c.a.-TG mice were more marked than those in WT mice. Conclusion: In a new experimental COPD mouse model, p38 accelerates the development of emphysema.
Journal of Receptor and Signal Transduction Research 03/2014; 34(4). DOI:10.3109/10799893.2014.896380 · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Preeclampsia is a serious complication during pregnancy, and recent epidemiological studies indicate the association between preeclampsia and cardiac morbidity and mortality during the postpartum period. Although the risk of cardiovascular diseases in the postpartum period is affected by lactation, its role in maternal heart with a history of preeclampsia remains unclear. In this study, we investigated postpartum change in cardiac remodeling and function of pregnancy-associated hypertensive (PAH) mice with and without lactation. The systolic blood pressure was increased in PAH mice at day 19 of gestation (E19) and was reduced to normal levels in both lactating and nonlactating (NL) groups in the postpartum period. Histological analyses revealed that cardiac hypertrophy and macrophage infiltration in PAH mice at E19 were improved in both lactating and NL groups at 4 weeks postpartum (4W-PP), while marked fibrosis remained. Increased mRNA expression of profibrotic genes and proinflammatory cytokines in PAH mice at E19 was significantly reduced in both lactating and NL groups at 4W-PP. Echocardiographic analysis found no significant differences in fractional shortening between PAH mice and C57BL/6J mice at E19. On the other hand, at 4W-PP, NL PAH mice showed normal fractional shortening, but lactating PAH mice exhibited significant decreases in cardiac contractility compared with NL PAH mice. These results show that cardiac remodeling induced by hypertension during pregnancy are improved in the postpartum period except fibrosis, whereas lactation induces cardiac contractile dysfunction in mice with a history of pregnancy-associated hypertension.
[Show abstract][Hide abstract] ABSTRACT: One of the mitogen-activated protein kinases, p38, has been found to play a crucial role in various inflammatory responses.
In this study, we analyzed the roles of p38α in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis
(EAE). p38α+/− mice (p38α−/− showed embryonic lethality) showed less severe neurological signs than WT mice. Adoptive transfer of lymph node cells (LNC)
from sensitized WT mice with MOG(35–55) to naive WT-induced EAE was much more severe compared with the case using LNC from
sensitized p38α+/− mice. Comprehensive analysis of cytokines from MOG(35–55)-challenged LNC by Western blot array revealed that production of
IL-17 was significantly reduced by a single copy disruption of the p38α gene or a p38 inhibitor. Likewise, by a luciferase reporter assay, an electrophoresis mobility shift assay, and characterization
of the relationship between p38 activity and IL-17 mRNA expression, we confirmed that p38 positively regulates transcription
of the Il17 gene. Furthermore, oral administration of a highly specific p38α inhibitor (UR-5269) to WT mice at the onset of EAE markedly
suppressed the progression of EAE compared with a vehicle group. These results suggest that p38α participates in the pathogenesis
of EAE through IL-17 induction.