Necroptosis is a genetically regulated form of necrotic cell death that has emerged as an important pathway in human disease. The necroptosis pathway is induced by a variety of signals, including death receptor ligands, and regulated by receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) and mixed-lineage kinase domain–like pseudokinase (MLKL), which form a regulatory necrosome complex. RIPK3-mediated phosphorylation of MLKL executes necroptosis. Recent studies, using animal models of tissue injury, have revealed that RIPK3 and MLKL are key effectors of injury propagation. This Review explores the functional roles of RIPK3 and MLKL as crucial pathogenic determinants and markers of disease progression and severity in experimental models of human disease, including acute and chronic pulmonary diseases; renal, hepatic, cardiovascular, and neurodegenerative diseases; cancer; and critical illness.
Mary E. Choi, David R. Price, Stefan W. Ryter, Augustine M. K. Choi
Respiratory diseases are among the leading causes of death and disability worldwide. However, the pathogenesis of both acute and chronic lung diseases remains incompletely understood. As a result, therapeutic options for important clinical problems, including acute respiratory distress syndrome and chronic obstructive pulmonary disease, are limited. Research efforts have been held back in part by the difficulty of modeling lung injury in animals. Donor human lungs that have been rejected for transplantation offer a valuable alternative for understanding these diseases. In 2007, our group developed a simple preparation of an ex vivo–perfused single human lung. In this Review, we discuss the availability of donor human lungs for research, describe the ex vivo–perfused lung preparation, and highlight how this preparation can be used to study the mechanisms of lung injury, to isolate primary cells, and to test novel therapeutics.
James T. Ross, Nicolas Nesseler, Jae-Woo Lee, Lorraine B. Ware, Michael A. Matthay
Inflammatory arthritis encompasses a set of common diseases characterized by immune-mediated attack on joint tissues. Most but not all affected patients manifest circulating autoantibodies. Decades of study in human and animal arthritis have identified key roles for autoantibodies in immune complexes and through direct modulation of articular biology. However, joint inflammation can arise because of pathogenic T cells and other pathways that are antibody-independent. Here we review the evidence for these parallel tracks, in animal models and in humans, to explore the range of mechanisms engaged in the pathophysiology of arthritis and to highlight opportunities for targeted therapeutic intervention.
Margaret H. Chang, Peter A. Nigrovic
Small heat shock proteins (sHSPs) comprise an important protein family that is ubiquitously expressed, is highly conserved among species, and has emerged as a critical regulator of protein folding. While these proteins are functionally important for a variety of tissues, an emerging field of cardiovascular research reveals sHSPs are also extremely important for maintaining normal cardiac function and regulating the cardiac stress response. Notably, numerous mutations in genes encoding sHSPs have been associated with multiple cardiac diseases. sHSPs (HSPB5, HSPB6, and HSPB8) have been described as mediating chaperone functions within the heart by interacting with the cochaperone protein BCL-2–associated anthanogene 3 (BAG3); however, recent reports indicate that sHSPs (HSPB7) can perform other BAG3-independent functions. Here, we summarize the cardiac functions of sHSPs and present the notion that cardiac sHSPs function via BAG3-dependent or -independent pathways.
Xi Fang, Julius Bogomolovas, Christa Trexler, Ju Chen
Sepsis-induced acute respiratory distress syndrome (ARDS) has high morbidity and mortality and arises after lung infection or infection at extrapulmonary sites. An aberrant host response to infection leads to disruption of the pulmonary alveolar-capillary barrier, resulting in lung injury characterized by hypoxemia, inflammation, and noncardiogenic pulmonary edema. Despite increased understanding of the molecular biology underlying sepsis-induced ARDS, there are no targeted pharmacologic therapies for this devastating condition. Here, we review the molecular underpinnings of sepsis-induced ARDS with a focus on relevant clinical and translational studies that point toward novel therapeutic strategies.
Joshua A. Englert, Christopher Bobba, Rebecca M. Baron
In the skin, complex cellular networks maintain barrier function and immune homeostasis. Tightly regulated multicellular cascades are required to initiate innate and adaptive immune responses. Innate immune cells, particularly DCs and mast cells, are central to these networks. Early studies evaluated the function of these cells in isolation, but recent studies clearly demonstrate that cutaneous DCs (dermal DCs and Langerhans cells) physically interact with neighboring cells and are receptive to activation signals from surrounding cells, such as mast cells. These interactions amplify immune activation. In this review, we discuss the known functions of cutaneous DC populations and mast cells and recent studies highlighting their roles within cellular networks that determine cutaneous immune responses.
Tina L. Sumpter, Stephen C. Balmert, Daniel H. Kaplan
Our understanding of the molecular pathogenesis of childhood cancers has advanced substantially, but their fundamental causes remain poorly understood. Recently, multiple mechanisms of DNA damage and repair have been associated with mutations observed in human cancers. Here, we review the physiologic functions and oncogenic activities of transposable genetic elements. In particular, we focus on the recent studies implicating DNA transposases RAG1/2 and PGBD5 as oncogenic mutators that promote genomic rearrangements in childhood leukemias and solid tumors. We outline future studies that will be needed to define the contributions of transposons to mutational processes that become dysregulated in cancer cells. In addition, we discuss translational approaches, including synthetic lethal strategies, for identifying and developing improved clinical therapies to target oncogenic transposons and transposases.
Anton G. Henssen, Alex Kentsis
At the simplest level, obesity is the manifestation of an imbalance between caloric intake and expenditure; however, the pathophysiological mechanisms that govern the development of obesity and associated complications are enormously complex. Fibrosis within the adipose tissue compartment is one such factor that may influence the development of obesity and/or obesity-related comorbidities. Furthermore, the functional consequences of adipose tissue fibrosis are a matter of considerable debate, with evidence that fibrosis serves both adaptive and maladaptive roles. Tissue fibrosis itself is incompletely understood, and multiple cellular and molecular pathways are involved in the development, maintenance, and resolution of the fibrotic state. Within the context of obesity, fibrosis influences molecular and cellular events that relate to adipocytes, inflammatory cells, inflammatory mediators, and supporting adipose stromal tissue. In this Review, we explore what is known about the interplay between the development of adipose tissue fibrosis and obesity, with a view toward future investigative and therapeutic avenues.
Ritwik Datta, Michael J. Podolsky, Kamran Atabai
The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries. The focus of our review is cancer associated fibroblast (CAF) cellular heterogeneity and plasticity and the acellular matrix components that accompany these cells. We explore how similarities and differences between healing wounds and tumor stroma continue to evolve as research progresses, shedding light on possible therapeutic targets that can result in innovative stromal-based treatments for cancer.
Deshka S. Foster, R. Ellen Jones, Ryan C. Ransom, Michael T. Longaker, Jeffrey A. Norton
The disabling degenerative disease osteoarthritis (OA) is prevalent among the global population. Articular cartilage degeneration is a central feature of OA; therefore, a better understanding of the mechanisms that maintain cartilage homeostasis is vital for developing effective therapeutic interventions. MicroRNAs (miRs) modulate cell signaling pathways and various processes in articular cartilage via posttranscriptional repression of target genes. As dysregulated miRs frequently alter the homeostasis of articular cartilage, modulating select miRs presents a potential therapeutic opportunity for OA. Here, we review key miRs that have been shown to modulate cartilage-protective or -destructive mechanisms and signaling pathways. Additionally, we use an integrative computational biology approach to provide insight into predicted miR gene targets that may contribute to OA pathogenesis, and highlight the complexity of miR signaling in OA by generating both unique and overlapping gene targets of miRs that mediate protective or destructive effects. Early OA detection would enable effective prevention; thus, miRs are being explored as diagnostic biomarkers. We discuss these ongoing efforts and the applicability of miR mimics and antisense inhibitors as potential OA therapeutics.
Helal Endisha, Jason Rockel, Igor Jurisica, Mohit Kapoor
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