Pharmacological approach to restoring steroid sensitivity in respiratory diseases / 中国药理学与毒理学杂志

Inhaled corticosteroid is the first-line controller for asthma and COPD. However, about 10% of the asthmatics (severe/refractory asthma) and most of the COPD patients are resistant to the beneficial effects of corticosteroids.There is a pressing unmet medical need to develop novel therapeu-tic agents to restore corticosteroid efficacy in affected patients. There have been reports showing the promise of theophylline and rapamycin in reversing steroid resistance in COPD. Our laboratory has demonstrated that andrographolide, a bioactive diterpenoid lactone isolated from the plant Androgra-phis paniculata, is an effective anti-inflammatory and anti-oxidative compound in both asthma and COPD experimental models. In a severe asthma mouse model using combined IFN-γ/LPS exposure, production of IL-27 and methacholine-induced airway hyperresponsiveness (AHR) were found to be corticosteroid-resistant.Andrographolide was found to restore the anti-inflammatory effect of dexameth-asone in LPS/IFN-γ-induced IL-27 levels in bronchoalveolar lavage(BAL)fluid and AHR in mice.LPS/IFN-γ markedly reduced the nuclear level of histone deacetylase-2 (HDAC2), an essential epigenetic enzyme that mediates corticosteroid anti-inflammatory actions. Andrographolide significantly restored nuclear HDAC2 levels and diminished total HAT/HDAC activity ratio in mouse lungs exposed to LPS/IFN-γ, probably via suppression of PI3K/Akt/HDAC2 phosphorylation and up-regulation of the antioxi-dant transcription factor Nrf2 level. In a cigarette smoke (CS)-induced COPD model, andrographolide markedly restored dexamethasone actions in inhibiting CS-induced lung neutrophilia.In addition,androgra-pholide facilitated dexamethasone actions to suppress BAL fluid IL-6, IL-1b, KC and IL-17 levels. In lung lysates, andrographolide markedly restored total nuclear HDAC activity. The complete steroid re-sensitization mechanism of andrographolide remains to be unraveled. Nevertheless, our existing data strongly implicate a potentially novel steroid re-sensitizing activity of andrographolide in both severe asthma and COPD models.

Prediction of differential creatinine clearance in chronically obstructed kidneys by non-contrast helical computerized tomography

PURPOSE: We investigate the use of non-contrast helical computerized tomography (NCHCT) in the measurement of differential renal parenchymal volume as a surrogate for differential creatinine clearance (CrCl) for unilateral chronically obstructed kidney. MATERIALS AND METHODS: Patients with unilateral chronically obstructed kidneys with normal contralateral kidneys were enrolled. Ultrasonography (USG) of the kidneys was first done with the cortical thickness of the site with the most renal substance in the upper pole, mid-kidney, and lower pole of both kidneys were measured, and the mean cortical thickness of each kidney was calculated. NCHCT was subsequently performed for each patient. The CT images were individually reviewed with the area of renal parenchyma measured for each kidney. Then the volume of the slices was summated to give the renal parenchymal volume of both the obstructed and normal kidneys. Finally, a percutaneous nephrostomy (PCN) was inserted to the obstructed kidney, and CrCl of both the obstructed kidney (PCN urine) and the normal side (voided urine) were measured two 2 after the relief of obstruction. RESULTS: From March 1999 to February 2001, thirty patients were enrolled into the study. Ninety percent of them had ureteral calculi. The differential CrCl of the obstructed kidney ( percentCrCl) was defined as the percentage of CrCl of the obstructed kidney as of the total CrCl, measured 2 weeks after relief of obstruction. The differential renal parenchymal volume of the obstructed kidney ( percentCTvol) was the percentage of renal parenchymal volume as of the total parenchymal volume. The differential USG cortical thickness of the obstructed kidney ( percentUSGcort) was the percentage of mean cortical thickness as of the total mean cortical thickness. The Pearson's correlation coefficient (r) between percentCTvol and percentCrCl and that between percentUSGcort and percentCrCl were 0.756 and 0.543 respectively. The regression line was percentCrCl = (1.00) x percentCTvol - 14.27. The percentCTvol overestimated the differential creatinine clearance by about 14 percent, but the correlation is good. CONCLUSION: The differential renal parenchymal volume measured by NCHCT provided a reasonable prediction of differential creatinine clearance in chronically obstructed kidneys.

Effects of inhibitors of the tyrosine kinase signaling cascade on an in vitro model of allergic airways.

It has been shown that activation of protein tyrosine kinases (PTKs) is the earliest detectable signaling response to FcepsilonRI cross-linking on mast cells. Following tyrosine kinase activation, a family of mitogen-activated protein kinases (MAPKs) was found to be activated as well. Activation of this PTK signaling cascade will lead to mast cell degranulation. This review summarizes our recent studies on the role of PTK signaling cascade in an in vitro guinea pig model of allergic asthma using PTK inhibitors, genistein and tyrphostin 47, and MAPK kinase inhibitor, PD098059. Inhibitors of the PTK and MAPK signaling pathways significantly attenuated the ovalbumin (OVA)-induced bronchial anaphylactic contraction and enhanced relaxation of constricted airways, respectively, and substantially blocked the release of histamine and peptidoleukotrienes from chopped lung preparations induced by OVA. Based upon their substantial inhibitory effects on the Schultz-Dale reaction, further examination on the potential anti-asthmatic effects of PTK cascade inhibitors in an in vivo model of allergic asthma is recommended.