Hui-Fang Tang

Zl-n-91, a selective phosphodiesterase 4 inhibitor, suppresses inflammatory response in a COPD-like rat model.

Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by poorly reversible airflow limitation induced by cigarette smoking and/or other noxious particle and gases. Phosphodiesterase (PDE) 4 inhibitors are known to elevated cAMP concentrations in inflammatory cells, leading to inhibition of inflammatory response, relaxation of smooth muscle in the airway, and modulation of sensory nerves in the lung as well. To investigate whether Zl-n-91, a new selective PDE4 inhibitor, could decrease inflammation and improve lung function in a COPD-like rat model, male Sprague-Dawley rats are used to challenge with lipopolysaccharide (LPS) and cigarette smoking (CS) exposure to induce COPD-like animal model. Administration of Zl-n-91 at different dosages results in decreases of inflammatory cell in bronchoalveolar lavage fluid (BALF) as compared with vehicle treatment. Zl-n-91 at 0.03, 0.3 or 3mg/kg not only dose-dependently inhibited PDE4 activity, but also decreased MMP-9 level in lungs and improved dynamic compliance (C(dyn)) as compared with vehicle treatment. Therefore, Zl-n-91 could inhibit inflammatory responses in rats after cigarette smoking exposure and LPS challenge, and it could be of some therapeutic potential as an alternative medicine in treatment of pulmonary diseases such as COPD.

Compound edaravone alleviates lipopolysaccharide (LPS)-induced acute lung injury in mice

Acute lung injury (ALI) represents an unmet medical need with an urgency to develop effective pharmacotherapies. Compound edaravone, a combination of edaravone and borneol, has been developed for treatment of ischemia stroke in clinical phase III study. The purpose of the present study is to investigate the anti-inflammatory effect of compound edaravone on lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 cells and the therapeutic efficacy on LPS-induced ALI in mice. Edaravone and compound edaravone concentration-dependently decreased LPS-induced interleukin-6 (IL-6) production and cyclooxygenase-2 (COX-2) expression in RAW264.7 cells. The efficiency of compound edaravone was stronger than edaravone alone. In the animal study, compound edaravone was injected intravenously to mice after intratracheal instillation of LPS. It remarkably alleviated LPS-induced lung injury including pulmonary histological abnormalities, polymorphonuclear leukocyte (PMN) infiltration and extravasation. Further study demonstrated that compound edaravone suppressed LPS-induced TNF-α and IL-6 increase in mouse serum and bronchoalveolar lavage (BAL) fluid, and inhibited LPS-induced nuclear factor-κB (NF-κB) activation and COX-2 expression in mice lung tissues. Importantly, our findings demonstrated that the compound edaravone showed a stronger protective effect against mouse ALI than edaravone alone, which suggested the synergies between edaravone and borneol. In conclusion, compound edaravone could be a potential novel therapeutic drug for ALI treatment and borneol might produce a synergism with edaravone.

Effects of local anesthetics on contractions of pregnant and non-pregnant rat myometrium in vitro.

In order to determine whether local anesthetics directly affect the propagation and strength of myometrial contractions, we compared the effects of bupivacaine, ropivacaine, lidocaine and tetracaine on the contractions of myometrium isolated from pregnant and non-pregnant rats. Full-thickness myometrial strips were obtained from 18- to 21-day pregnant and non-pregnant Sprague-Dawley rats and incubated in an organ bath. When spontaneous contractions became regular, strips were exposed to cumulative concentrations of the four local anesthetics ranging from 0.01 to 300 μmol/L and the amplitude and frequency of contraction were recorded. All four compounds caused a concentration-dependent inhibition of the contractility of pregnant and non-pregnant uterine muscle. In pregnant myometrium, the concentration that caused 50% inhibition (IC(50)) was 100 μmol/L for bupivacaine, 157 μmol/L for ropivacaine, > 1000 μmol/L for lidocaine, and 26.3 μmol/L for tetracaine. In non-pregnant myometrium, the IC(50) was 26.9 μmol/L for bupivacaine, 40 μmol/L for ropivacaine, 384 μmol/L for lidocaine, and 7.4 μmol/L for tetracaine. These results suggested that local anesthetics do inhibit myometrial contractions in pregnant and non-pregnant rats in a concentration-dependent manner.

Effects of Inactivated Bordetella pertussis on Phosphodiesterase in the Lung of Ovalbumin Sensitized and Challenged Rats

This paper indicated that inactivated Bordetella pertussis (iBp) can enhance the lung airway hyperreactivity of the rats sensitized and challenged with OVA. The mechanisms were involved in the upregulation of cAMP-PDE activity and PDE4A, PDE4D, and PDE3 gene expression in the lungs. But only PDE4 activity was different between the OVA and OVA+iBp groups, and PDE4D expression was significantly increased in iBp rats alone. So, our data suggested that cosensitization with OVA and iBp affects lung airway reactivity by modulating the lung cAMP-PDE activity and PDE4D gene expression.

Potential role of phosphodiesterases in the development of multiple organ dysfunction

Background. Multiple organ dysfunction syndrome (MODS) is the commonest cause of death in intensive care units. Growing recognition of this disease in the last 30 years may be due to advances in early resuscitation unmasking delayed sequelae in those who would have died previously. MODS occurs after shock of various etiologies, especially sepsis, and may be the result of overactivated systemic inflammation. As yet, therapies directed at preventing or improving MODS have not dramatically altered the outcomes. Phosphodiesterases (PDEs) are enzymes primarily responsible for the breakdown of the intracellular second messengers adenosine 3′,5′-cyclic monophosphate and guanosine 3′,5′-cyclic monophosphate. Although these enzymes were initially described many years ago, new families and subtypes of PDEs continue to be discovered. There is also a wide variation in the distribution of PDEs among tissues or species. This tissue-specific distribution has led to differential pharmacologic actions of PDE inhibitors. E...