oa Editorial [Hot Topic: Why Apoptosis in Pediatric Disorders? (Guest Editor: Eltyeb Abdelwahid)]

Apoptosis (Programmed Cell Death) in Pediatric Disorders One of the biggest challenges in modern medicine is the comprehension of programmed cell death (apoptosis) in the context of pediatric diseases. Apoptosis is a highly regulated process that is critically important for cellular self-destruction in a variety of normal and disease situations. The term apoptosis was coined by Kerr and colleagues in 1972, after the Greek word meaning leaves falling from a tree in the autumn, to describe a tightly regulated cell suicide program under physiological conditions [1]. Apoptotic cell is recognized by characteristic features [2] including chromatin condensation and nuclear fragmentation (pyknosis), plasma membrane blebbing, and cell shrinkage. The apoptotic cells break into apoptotic bodies, which are engulfed by phagocytosis without inflammatory response [3] (Fig. 1). Many of apoptotic changes are caused by the activation of a family of intracellular cysteine proteases called caspases [4]. Now, almost four decades later, we understand much about the control of this machinery but need to translate this knowledge into clinical practice and drug discovery. Apoptosis eliminates unwanted or unnecessary cells and thus modulates pathological contexts [5]. Deregulation of apoptosis may cause diseases either by insufficient or excessive programmed cell death [5-7]. The emerging advances in developmental biology, genomics & genetics, and cell immunology & biology, combined with the development of appropriate animal models, have offered tremendous support for the proposed roles for programmed cell death in pediatric disorders. Future studies using both animal models and clinical specimens hold the promise of scientific groundwork for medical interventions [8-17]. Although advances in elucidating the regulation of apoptosis have laid the foundation for a deeper understanding of the pathophysiology of many pediatric diseases, we still need to know much about how the apoptotic machinery is connected to many aspects of developmental and disease pathways in the human body [18-20]. Apoptotic cell death occurs via tightly controlled and well-established extrinsic and intrinsic cellular diverse cascades [21-23]. There are now growing lists of both upstream and downstream mediators of both extrinsic and intrinsic apoptosis. The extrinsic pathway of apoptosis is initiated by the binding of death ligands of the tumor necrosis factor (TNF) superfamily, e.g. Fas ligand, TNF alpha or TNF-related apoptosis-inducing ligand (TRAIL), to their corresponding receptors on the surface of the cell, such as CD95 (Fas) or the TNF receptor [24-28]. This recruits the intracellular death inducing signaling complex (DISC). The DISC activates the initiator caspases, particularly caspase-8, leading to activation of downstream caspases, like caspases 9 and 3, and eventually to apoptotic cell death. It is now well established that the extrinsic pathway plays important role in controlling growth of cancer cells. The intrinsic (mitochondrial) pathway of apoptosis is regulated by pro and anti-apoptotic proteins of the Bcl-2 (B-cell lymphoma-2) family proteins [29, 30]. Upon apoptosis induction, cytochrome C is released from the mitochondria into the cytosol where it promotes the assembly of a caspase-activating complex termed the apoptosome [31- 33]. The apoptosome is a multimeric protein complex containing Apaf-1, cytochrome c, and caspase-9. Upon binding to the apoptosome, caspase-9 is activated, and subsequently activates the downstream effector caspases, leading to proteolysis and apoptotic cell death. There are now various strategies that can be used to prevent or induce cell death or to develop drugs that can block pro- or antiapoptotic factors. Furthermore, the promising new pharmaceutical strategies to treat deregulated gene-directed processes may provide advances in the control of various pediatric diseases including cancer, congenital malformations, immune system diseases, metabolic disorders and other diseases of various systems. Thus, the contribution of apoptosis to the pathogenesis of various diseases and abnormalities is likely to be modulated by targeting specific factors involved in the entire process.....