Acute lung injury (ALI) is an acute hypoxic respiratory insufficiency caused by various intra- and extrapulmonary injury factors. Presently, excessive inflammation in the lung and the apoptosis of alveolar epithelial cells are considered to be the key factors in the pathogenesis of ALI. Hypoxia-inducible factor-1 (HIF-1) is an oxygen-dependent conversion activator that is closely related to the activity of reactive oxygen species (ROS). HIF-1 has been shown to play an important role in ALI and can be used as a potential therapeutic target for ALI. This manuscript will introduce the progress of HIF-1 in ALI and explore the feasibility of applying inhibitors of HIF-1 to ALI, which brings hope for the treatment of ALI.

/pdf/hypoxia-inducible-factor-1-a-potential-target-to-treat-acute-3ixe4jhyuf.pdf

Hypoxia-Inducible Factor-1: A Potential Target to Treat Acute Lung Injury.

Direct peritoneal resuscitation improves survival and decreases inflammation after intestinal ischemia and reperfusion injury

Effects of penehyclidine hydrochloride on severe acute pancreatitis-associated acute lung injury in rats.

Pyruvate is an energy substrate that has both inotropic and antioxidant properties. In this study, we tested the hypothesis that survivorship would be better after resuscitation with 1.7% sodium pyruvate than 0.9% sodium chloride in a profound hemorrhagic shock model. The study was performed in a blinded manner. Rats were randomly assigned into two groups (ten in each group), a sodium chloride resuscitation group and a sodium pyruvate resuscitation group. After a 60-min shock period, we infused 80 ml/kg of a resuscitation solution. We continuously monitored mean arterial pressure and heart rate for 50 min after resuscitation. We recognized death by the disappearance of blood pressure pulsation and precordial movement. We performed a comparison of survivorship at 50 min post resuscitation using a Z-test of proportions. Nine (90%) of the animals that received sodium pyruvate were living 50 min after resuscitation, whereas only three (30%) of the animals that received sodium chloride survived to the same time point. We conclude that sodium pyruvate is better than sodium chloride as a resuscitation solution in a model of profound hemorrhagic shock.

Sodium pyruvate is better than sodium chloride as a resuscitation solution in a rodent model of profound hemorrhagic shock

Ischemic heart disease is a major cause of mortality and disability worldwide. Timely reperfusion is currently the most effective method of treating ischemic heart disease; however, abrupt reperfusion may cause ischemia/reperfusion (I/R) injury. Apoptosis serves an important role in the progression of myocardial I/R injury and it has been demonstrated that the mitochondria are the center of regulation for apoptosis. Penehyclidine hydrochloride (PHC) is used during surgery and has recently been identified as a new type of anticholinergic drug. It has been demonstrated in vivo that pretreatment with PHC reduces myocardial apoptosis in rat hearts. The present study aimed to investigate the effects of PHC post-conditioning on myocardial cell apoptosis in a rat model of myocardial I/R and to determine whether the mitochondria-induced pathway was activated. Male Wistar rats were evenly and randomly categorized into 4 experimental groups as follows: i) Sham group; ii) I/R group; iii) PHC+sham group; and iv) PHC+I/R group. A PHC (1 mg/kg) post-conditioning approach (5 min before reperfusion) was used in addition to I/R in the PHC-treated groups. Following 3 h reperfusion, flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed to measure myocardial cell apoptosis. A JC-1 staining method was performed to measure the mitochondrial membrane potential of myocardial cells. The expression of Bax, Bcl-2, voltage dependent anion-selective channel protein 1 (VDAC1), cytosol cytochrome c (cyt-c) and cleaved caspase-3 was analyzed using western blotting. PHC post-conditioning significantly reduced apoptosis in cardiomyocytes, significantly downregulated the expression of Bax, VDAC1, cytosol cytochrome c and cleaved caspase-3 but significantly upregulated the expression of Bcl-2. PHC post-conditioning also restored the mitochondrial membrane potential. Thus, the present study demonstrated that PHC post-conditioning protects cardiomyocytes against apoptosis in the rat model of myocardial I/R by inhibiting the mitochondria-induced intrinsic pathway.

/pdf/penehyclidine-hydrochloride-post-conditioning-reduces-1nza7fdrwx.pdf

Penehyclidine hydrochloride post-conditioning reduces ischemia/reperfusion-induced cardiomyocyte apoptosis in rats.

Objective We explored the effects of direct peritoneal resuscitation with pyruvate-peritoneal dialysis solution (PDS) following intravenous resuscitation (VR) on intestinal ischemia-reperfusion injury in rats with hemorrhagic shock (HS). Methods Fifty rats were randomly assigned equally to five groups. In group sham, a surgical operation was performed on rats without shock or resuscitation. In group VR, rats were subjected only to VR. In groups NS, LA, and PY, direct peritoneal resuscitation was performed with normal saline (NS), lactate-based PDS (Lac-PDS), and pyruvate-based PDS (Pyr-PDS), respectively, after VR. Mean arterial pressure was monitored in the right common carotid artery. Two hours after resuscitation, the lactate level in arterial blood and the wet weight/dry weight ratio of the intestine were determined. The intestinal mucosal damage index was estimated, and ultrastructural changes in the intestinal mucosa were observed. Malondialdehyde, myeloperoxidase, nitric oxide, and tumor necrosis factor α levels were also measured. Results Two hours after HS and resuscitation, the increase in arterial blood lactate and intestinal wet weight/dry weight ratio declined significantly in rats from Groups LA and PY compared with groups VR and NS, whereas group PY was more advantageous in the changes of these parameters. The intestinal mucosal damage index and ultrastructural changes were also improved in groups LA and PY when compared with groups VR and NS. Protection was more apparent with Pyr-PDS than Lac-PDS. Hemorrhagic shock resulted in a significant increase in malondialdehyde levels and myeloperoxidase activity and was accompanied by overexpression of tumor necrosis factor α and a reduction in nitric oxide levels. These changes were significantly attenuated by Lac-PDS and Pyr-PDS at 2 h after resuscitation, and Pyr-PDS showed more effective protection for the intestine than Lac-PDS. Conclusions Direct peritoneal resuscitation with Lac-PDS and Pyr-PDS after VR alleviated intestinal injury from HS in rats, and Pyr-PDS was superior to Lac-PDS in its protective effect. Mechanisms of action might include the elimination of free oxygen radicals, reduction of neutrophil infiltration, inhibition of the inflammatory response, and regulation of intestinal mucosal blood flow and barrier function.

Protection against intestinal injury from hemorrhagic shock by direct peritoneal resuscitation with pyruvate in rats.

Objective
To evaluate the role of β-arrestin-1 in inhibition of endotoxin-induced activation of nuclear factor kappa B (NF-κB) in human pulmonary microvascular endothelial cells (HPMVECs) by penehyclidine hydrochloride (PHC).


Methods
HPMVECs were seeded in 6-well plates (2 ml/hole) or in culture flasks (4 ml/flask) at the density of 1×105/ml, and were randomly divided into 5 groups(n=20 each) using a random number table: empty plasmid transfection group (group C), lipopolysaccharide (LPS) + empty plasmid transfection group (group LPS), PHC + LPS + empty plasmid transfection group (group P+ LPS), LPS + β-arrestin-1 gene-shRNA transfection group (group LPS+ shRNA) and PHC + LPS + β-arrestin-1 gene-shRNA transfection group (group P+ LPS+ shRNA). HPMVECs were transfected with empty plasmid 1.5 μg or with plasmid containing 15 nmol/L β-arrestin-1gene-shRNA.At 24 h of incubation, PHC with the final concentration of 2 μg/ml was added, the cells were incubated for 1 h, LPS with the final concentration of 0.1 μg/ml was then added, and the cells were continuously incubated for another 1 h. The supernatant was collected to measure the activity of lactic dehydrogenase (LDH). The cell suspension was collected for determination of vascular cell adhesion molecule-1 (VCAM-1) expression and NF-κB activities and NF-κB inhibitor I-κB and β-arrestin-1expression.


Results
Compared with group C, the activities of LDH in supernatant were increased, VCAM-1 expression was up-regulated, NF-κB activity was significantly increased, and I-κB and β-arrestin-1 expression was down-regulated in LPS and LPS+ shRNA groups.Compared with group LPS, the activities of LDH in supernatant were decreased, VCAM-1 expression was down-regulated, NF-κB activity was significantly decreased, and I-κB and β-arrestin-1 expression was up-regulated in group P+ LPS, and no significant change was found in the parameters mentioned above in group P+ LPS+ shRNA.Compared with group P+ LPS, the activities of LDH in supernatant were increased, VCAM-1 expression was up-regulated, NF-κB activity was significantly increased, and I-κB and β-arrestin-1 expression was down-regulated in group P+ LPS+ shRNA.


Conclusion
PHC inhibits endotoxin-induced activation of NF-κB in HPMVECs completely through up-regulating β-arrestin-1 expression.


Key words: 
Arrestins; Cholinergic agents; NF-kappa B; Endothelial cells; Capillaries; Lung; Endotoxemia

Roles of β-arrestin-1 in inhibition of endotoxin-induced activation of NF-κB in human pulmonary microvascular endothelial cells by penehyclidine hydrochloride

Penehyclidine hydrochloride decreases pulmonary microvascular permeability by upregulating beta arrestins in a murine cecal ligation and puncture model.

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Protection against intestinal injury from hemorrhagic shock by direct peritoneal resuscitation with pyruvate in rats.

Roles of β-arrestin-1 in inhibition of endotoxin-induced activation of NF-κB in human pulmonary microvascular endothelial cells by penehyclidine hydrochloride

Penehyclidine hydrochloride decreases pulmonary microvascular permeability by upregulating beta arrestins in a murine cecal ligation and puncture model.