RIP3-dependent necroptosis contributes to the pathogenesis of chronic obstructive pulmonary disease.

Necroptosis has emerged as a potential mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we found that markers of necroptosis, including high mobility group box 1 release and phosphorylation of mixed lineage kinase domain-like protein (p-MLKL), were markedly induced in the late stage of cigarette smoking-induced (CS-induced) emphysema in mouse lung tissue as well as in lung epithelial cells and organoids with higher dosage of or more prolonged exposure to cigarette smoking extract (CSE). Apoptotic signals were also detected and maximally induced in the early stage of CS-exposed mice and CSE-treated epithelial cells. Inhibition of apoptosis by Z-VAD, a pan-caspase inhibitor, switched the cellular stress to enhanced necroptosis in lung epithelial cells and organoids treated with CSE. Depletion or inhibition of receptor-interacting protein kinase 3 (RIP3) or MLKL attenuated the CSE-induced cell death, suggesting that necroptosis contributes to CSE-induced cell death. Silencing or inhibition of RIP1 had no protective effect, indicating a RIP1-independent RIP3 activation pathway. CSE-induced necroptosis released more damage-associated molecular patterns and evoked greater engulfment but slower clearance by bone marrow-derived macrophages, leading to enhanced expression of proinflammatory cytokines Tnfα and Il6. Finally, our in vivo data verified that inhibition of necroptosis by RIP3 inhibitor GSK'872 protected mice from CS-induced emphysema and suppressed the lung inflammation. In conclusion, we provide evidence that necroptosis contributes to the pathogenesis of COPD. Targeting RIP3 and its downstream pathway may be an effective therapy for COPD.

Continuous infusions of terbutaline in asthma - a review.

BACKGROUND: After the safety issues raised by the Salmeterol Multicenter Asthma Research Trial, concerns persist about the safety of agents that cause prolonged ß-adrenoceptor stimulation in asthmatic patients. We therefore decided to revisit and review the use of continuous subcutaneous infusions of terbutaline (CSIT)-a treatment often reserved for those with severe and refractory disease. RESULTS: Original studies from the 1980s included 26 patients and showed that CSIT was well tolerated with predominately cutaneous side effects despite maintaining very high serum levels of terbutaline. CSIT led to improved outcomes in approximately 75% of patients which included rises in lowest daily peak expiratory flow rate (PEFR), diminution in diurnal variation, reduction in other medication requirements, and subjective opinion of symptoms. Almost all patients demonstrating an improvement had a wide variation in their pretreatment PEFRs. However, in a retrospective follow-up of 42 patients, the only outcome to be significantly improved by CSIT was that of mean hospital admissions (p = .031). CSIT is theorized to stimulate a discrete set of ß-receptors not accessible by the inhaled route as further increases in Forced expiratory volume in one second (FEV(1)) occur with concurrent nebulized therapy. CONCLUSION: Although some findings are encouraging, they are drawn from small observational studies done at a time when the standard management of asthma was quite different from today. No randomized controlled trials exist for the use of CSIT, which remains off-license for the treatment of asthma in the United Kingdom. Clearly, prospective well-powered studies are required to fully ascertain its potential benefits and safety profile-something that is unlikely to occur given that the use of CSIT remains low and appears to be declining.