Background/Aims: Acute lung injury (ALI) often predisposes acute respiratory distress syndrome (ARDS) in humans, and is featured with neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Although the pathogenesis of ALI is relatively well studied, the knowledge on the molecular regulation of the post-ALI lung recovery are poorly understood. Methods: Here, we used a widely applied bleomycin-induced ALI model to study the molecular mechanisms that underlie the post-ALI lung recovery in mice. We analyzed Sox9 expression in mouse lung by RT-qPCR, Western blot and immunohistochemistry. We analyzed miR-101 levels in mouse lung by RT-qPCR. We inhibited Sox9 in mouse lung by expressing either shRNA for Sox9 or miR-101, and analyzed the effects of Sox9 suppression on lung recovery. Results: We detected a significant increase in Sox9 protein but not mRNA, and a signifcant decrease in miR-101 levels in the mouse lung after ALI. MiR-101 was found to target 3'-UTR of Sox9 mRNA to inhibit its expression. Sox9 inhibition by either shRNA for Sox9 or by miR-101 further impaired the functional recovery of the lung after ALI. Conclusion: Our data suggest that Sox9 activation is essential for the recovery of lung function after ALI, which highlights a previously unappreciated mechanism that controls the post-ALI lung recovery.
Rheumatoid arthritis (RA) is a chronic, inflammatory disease that afflicts 1-2% of the world population, characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. The treatment goals of RA should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Current treatment can be divided into four classes, namely general analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs) and biological agents (tumor-necrosis factor modifiers). However, gastrointestinal (GI) side effects of NSAIDs cannot be neglected, direct joint injections of glucocorticoids cannot be injected more than once every 3 months, synthetic DMARDs is far from optimal and only minority of patients achieved longterm remission, the biologics are very expensive to manufacture, need to be injected, and can cause allergic reactions. An alternative and good approach to the treatment of this disease is to lower the levels of tumour necrosis factor-α (TNF-α) in RA, which can be achieved by selectively inhibiting the tumour necrosis factor-α converting enzyme (TACE) that generate these cytokines using cheaper small molecules. This review focuses on the current status of selective small molecule inhibitors of TACE, with respect to lead compound search, inhibitors design approach, structure-activity relationship (SAR) and pharmacological studies in animals and humans. Through these methods, new hope is emerging for the treatment of RA through selective inhibition of TACE.
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