[Show abstract][Hide abstract] ABSTRACT: Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.
PLoS ONE 03/2015; 10(3):e0121615. DOI:10.1371/journal.pone.0121615 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bronchial asthma is characterized by allergic airway inflammation involving C-C chemokine receptor type 4 (CCR4)-positive Th2 cells. As such, we hypothesize that the disease can be alleviated by targeted-elimination of CCR4(+) cells. Thymus and activation-regulated chemokine (TARC)-PE38, a TARC fused the exotoxin fragment PE38 from Pseudomonas aeruginosa, has been shown to efficiently kill CCR4(+) cells by delivering the exotoxin fragment PE38 into CCR4(+) cells. To test our hypothesis, we examined whether TARC-PE38 could suppress allergic airway inflammation in a mouse model of house dust mite (HDM)-induced allergic airway inflammation.
We evaluated the effect of TARC-PE38 on the major characteristics of HDM-induced allergic airway inflammation. Airway hyperresponsiveness, lung histopathology, lung Th1/Th2 cell populations, and concentrations of Th1/Th2 cytokines in the lungs were assessed in HDM-sensitized and challenged mice in the presence and absence of TARC-PE38.
TARC-PE38 efficiently suppressed allergic airway inflammation by significantly reducing airway hyperresponsiveness, the overall area of inflammation, and goblet cell hyperplasia. In HDM-sensitized and challenged mice, TARC-PE38 specifically reduced the numbers of CCR4(+) cells. This reduction was associated with a significant decrease in the production of Th2 cytokines in the airway,and a decrease in the number of leukocytes, including macrophages, eosinophils and lymphocytes, within the subepithelial area of the lungs and airway lumen. TARC-PE38 had noeffect on Th1 cells.
Our data suggest that the elimination of CCR4(+) cells via TARC-PE38 treatment is sufficient to control allergic airway inflammation and airway hyperresponsiveness.
[Show abstract][Hide abstract] ABSTRACT: Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been reported to be associated with interstitial lung disorders, and their high incidence and mortality have become a matter of great concern, especially in Japan. In this study, we investigated the effect of gefitinib on different phases of radiation-induced lung disorders in an experimental model.
The thoraxes of Wistar rats were irradiated on day 1 with a single X-ray dose of 20 Gy, and gefitinib (50 mg/kg/day) was orally administered from day 1 to 14. The rat lungs were harvested on days 15 and 57 and the bronchoalveolar lavage (BAL) was performed.
Gefitinib treatment increased the infiltration of inflammatory cells, which produced more pro-inflammatory cytokines (IL-6, IL-1β), in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57.
In irradiated rats, gefitinib treatment augmented lung inflammation, including inflammatory cell infiltration and pro-inflammatory cytokine expression, while gefitinib treatment attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation.
The Journal of Medical Investigation 02/2012; 59(1-2):174-85. DOI:10.2152/jmi.59.174
[Show abstract][Hide abstract] ABSTRACT: We report a case of Churg-Strauss syndrome (CSS) in a patient with multiple cerebral infarctions and psychotic symptoms. A 67-year-old man presented a high-grade fever and delirium. He was clinically diagnosed with Churg-Strauss syndrome on the basis of the presence of asthma, neuropathy, blood eosinophilia, and increased myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) activities. Though multiple cerebral infarctions are irreversible, this patient's psychiatric symptoms improved with steroid treatment. Psychiatric symptoms associated with CSS are very rare.
Internal Medicine 01/2012; 51(3):301-3. DOI:10.2169/internalmedicine.51.6447 · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Platinum-doublet regimens and docetaxel as first- and second-line chemotherapy, respectively, are shown to prolong the survival of lung cancer patients in various randomized phase III studies. However, the evidence for the efficacy of chemotherapy for lung cancer in the clinical practice is still insufficient. In the present study, we investigated the effectiveness and safety of outpatient chemotherapy for lung cancer in the clinical practice. Ninety-four lung cancer cases were retrospectively analyzed. Among these cases, 67 (71.3%) were non-small cell lung cancer (NSCLC) and 27 (28.7%) were small cell lung cancer (SCLC). The response rates in SCLC and NSCLC patients were 55.6% (15/27) and 16.9% (11/65), respectively. Objective tumor response rates for the patients were found to decrease substantially with each line of treatment as described previously. All adverse events were well tolerated and no treatment-related death was observed. Median time to treatment failures (TTFs) of first-line treatment were 10.1 months and 4.8 months in SCLC and NSCLC, respectively. These findings indicate that even in the setting of clinical practice, the efficacy and safety of chemotherapy is strictly insured by the appropriate therapeutic management.
The Journal of Medical Investigation 08/2011; 58(3-4):219-26. DOI:10.2152/jmi.58.219
[Show abstract][Hide abstract] ABSTRACT: Nuclear factor (NF)-κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) β is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKβ-NF-κB pathway may be an ideal strategy for the management of airway remodelling.
We examined the effects of a newly synthesized IKKβ inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice.
A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined.
NF-κB activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-β, via inhibition of IKKβ. IMD-0354 inhibited IL-13 and IL-1β production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness.
IKKβ plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKβ inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.