Significance: Oxidative stress in the cell is characterized by excessive generation of reactive oxygen species (ROS). Superoxide (O₂^-) and hydrogen peroxide (H₂O₂) are the main ROS involved in the regulation of cellular metabolism. As our fundamental understanding of the underlying causes of lung disease has increased it has become evident that oxidative stress plays a critical role. Recent Advances: A number of cells in the lung both produce, and respond to, ROS. These include vascular endothelial and smooth muscle cells, fibroblasts, and epithelial cells as well as the cells involved in the inflammatory response, including macrophages, neutrophils, eosinophils. The redox system is involved in multiple aspects of cell metabolism and cell homeostasis. Critical Issues: Dysregulation of the cellular redox system has consequential effects on cell signaling pathways that are intimately involved in disease progression. The lung is exposed to biomechanical forces (fluid shear stress, cyclic stretch, and pressure) due to the passage of blood through the pulmonary vessels and the distension of the lungs during the breathing cycle. Cells within the lung respond to these forces by activating signal transduction pathways that alter their redox state with both physiologic and pathologic consequences. Future Directions: Here, we will discuss the intimate relationship between biomechanical forces and redox signaling and its role in the development of pulmonary disease. An understanding of the molecular mechanisms induced by biomechanical forces in the pulmonary vasculature is necessary for the development of new therapeutic strategies.

Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.