Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock.

Lipopolysaccharide (LPS), one of the most prominent pathogen-associated molecular patterns (PAMPs), activates macrophages, causing release of toxic cytokines (i.e. tumor necrosis factor (TNF)-α) that may provoke inflammation and endotoxin shock. Here, we tested the potential role of trametinib, a novel and highly potent MAPK/ERK kinase (MEK) inhibitor, against LPS-induced TNF-α response in monocytes, and analyzed the underlying mechanisms. We showed that trametinib, at nM concentrations, dramatically inhibited LPS-induced TNF-α mRNA expression and protein secretion in transformed (RAW 264.7 cells) and primary murine macrophages. In ex-vivo cultured human peripheral blood mononuclear cells (PBMCs), this MEK inhibitor similarly suppressed TNF-α production by LPS. For the mechanism study, we found that trametinib blocked LPS-induced MEK-ERK activation in above monocytes, which accounted for the defective TNF-α response. Macrophages or PBMCs treated with a traditional MEK inhibitor PD98059 or infected with MEK1/2-shRNA lentivirus exhibited a similar defect as trametinib, and nullified the activity of trametinib. On the other hand, introducing a constitutively-active (CA) ERK1 restored TNF-α production by LPS in the presence of trametinib. In vivo, mice administrated with trametinib produced low levels of TNF-α after LPS stimulation, and these mice were protected from LPS-induced endotoxin shock. Together, these results show that trametinib inhibits LPS-induced TNF-α expression and endotoxin shock probably through blocking MEK-ERK signaling.

Auricularia auricular-judae polysaccharide attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress and inflammation.

Auricularia auricular-judae polysaccharide (AAP) has shown a variety of pharmacological properties. In the present study, the role of AAP in acute lung injury (ALI) induced by lipopolysaccharide (LPS) was analyzed in rats to further explore the possible underlying mechanisms. Adult Sprague-Dawley rats were randomly assigned into the control, AAP, LPS and LPS plus AAP groups. Rats were injected with LPS (10 mg/kg, intraperitoneal) to induce ALI. Rats in the LPS plus AAP group were treated with AAP for 7 days before the induction of ALI. The protein concentration in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by the wet/dry (W/D) weight ratio. The myeloperoxidase (MPO) activity and malondialdehyde (MDA) level were assayed by MPO and MDA kits, respectively. The levels of inflammatory mediators, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, were assayed by the enzyme-linked immunosorbent assay method. Pathological changes of lung tissues were observed by hematoxylin and eosin staining. The data showed that treatment with AAP significantly improved LPS-induced lung pathological changes, attenuated protein concentration in the BALF, inhibited MPO activity and reduced the MDA level and lung W/D weight ratio. AAP also inhibited the release of TNF-α and IL-6 in blood. The results indicated that AAP has a protective effect on LPS-induced ALI in rats.

Misdiagnosis of aortic dissection: experience of 361 patients.

Aortic dissection (AD) is a life-threatening condition that requires immediate diagnosis and surgical correction. Patients with acute AD usually present clinically with an insignificant medical history, leading to a high probability of misdiagnosis. The aim of the present study was to investigate the number of misdiagnoses of patients with AD in order to understand this problem and to avoid future misdiagnosis in the emergency department. Clinical data from 361 patients with AD admitted between January 2003 and June 2008 were reviewed as part of a retrospective chart review. Diagnosis of AD was made using either chest x-ray, computed tomography, magnetic resonance imaging, or angiography. Fifty-one patients had an initial misdiagnosis (14.1%), later found to have experienced AD. The condition may clinically present in a varied number of manifestations, including syncope, chest pain, abdominal pain, back pain, acute congestive heart failure, or alternatively with minimal symptoms. Persons of any age can experience an AD, with key clinical manifestations of pain. Echocardiography can be used for primary examination of patients with suspected AD; however, a definite diagnosis is usually made using computed tomographic or magnetic resonance angiography. Care should be taken, particularly in the emergency department, to maintain a level of suspicion for AD diagnosis in order to avoid the potential for misdiagnosis.