ABSTRACT
Neutrophilic inflammation occurs during asthma exacerbation, and especially, in patients with steroid-refractory asthma, but the underlying mechanisms are poorly understood. Recently, a significant accumulation of neutrophil extracellular traps (NETs) in the airways of neutrophilic asthma has been documented, suggesting that NETs may play an important role in the pathogenesis. In this study, we firstly demonstrated that NETs could induce human airway epithelial cell damage in vitro. In a mouse asthmatic model of neutrophil-dominated airway inflammation, we found that NETs were markedly increased in bronchoalveolar lavage (BAL), and the formation of NETs exacerbated the airway inflammation. Additionally, a small-molecule drug necrostatin-1 (Nec-1) shown to inhibit NETs formation was found to alleviate the neutrophil-dominated airway inflammation. Nec-1 reduced total protein concentration, myeloperoxidase activity, and the levels of inflammatory cytokines in BAL. Finally, further experiments proved that the inhibition of Nec-1 on NETs formation might be related to its ability to inhibiting mixed lineage kinase domain-like (MLKL) phosphorylation and perforation. Together, these results document that NETs are closely associated with the pathogenesis of neutrophilic asthma and inhibition of the formation of NETs by Nec-1 may be a new therapeutic strategy to ameliorate neutrophil-dominated airway inflammation.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Imidazoles/therapeutic use , Indoles/therapeutic use , Inflammation/drug therapy , Neutrophils/immunology , Protein Kinases/metabolism , Animals , Disease Models, Animal , Extracellular Traps/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Neutrophil Activation , PhosphorylationSubject(s)
Graft Survival/immunology , Heart Transplantation/immunology , Immunosuppressive Agents/pharmacology , Propylene Glycols/pharmacology , Animals , Drug Administration Schedule , Fingolimod Hydrochloride , Graft Survival/drug effects , Heart Transplantation/methods , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Microsurgery/methods , Sphingosine/analogs & derivatives , Time Factors , Transplantation, Homologous/immunologyABSTRACT
Apoptosis plays an essential role in maintaining cellular homeostasis during development, differentiation, and pathophysiological processes. In the immune system, recent investigations reveal that during the course of T-cell development in the thymus, negative selection of autoreactive immature T-cells is a typical apoptotic process. In addition, apoptosis is also involved in cytotoxic killing of target cells and the regulation of lymphocyte homeostasis during immune responses. Interestingly, recent evidence has suggested that cells dying by apoptosis are actively involved in immunosuppression in various circumstances. We have shown that apoptotic cells could inhibit the expression of CD69 during T-cell activation. Furthermore, apoptotic cells phagocytosed by macrophages and/or dendritic cells are immunosuppressive, a process likely mediated by the production of transforming growth factor-beta1. Since apoptosis is a common mechanism by which excessive cells in many tissues and organs are eliminated in various pathophysiological processes, we believe that further investigation into the mechanisms by which apoptotic cells affect the immune system will not only lead to a better understanding of the significance of apoptosis during immune responses, but will also provide novel strategies for the management of autoimmune diseases and transplantation.
Subject(s)
Apoptosis/physiology , Immune System/physiology , T-Lymphocytes/physiology , Autoimmune Diseases/immunology , Autoimmune Diseases/physiopathology , Humans , Immunosuppression Therapy , Liver/cytology , Liver/immunology , Liver/physiologyABSTRACT
The 4-year experience in the clinical usage of titanium nails in making internal fistula for hemodialysis in 428 cases (17,829 dialyses) is reported. The results were satisfactory and no obvious complications were found. Being simple in practice and having a high success rate and less complications, this method has been applied at 86 hospitals in China.
