Stop the Flow: A Paradigm for Cell Signaling Mediated by Reactive Oxygen Species in the Pulmonary Endothelium

Abstract

The lung endothelium is exposed to mechanical stimuli through shear stress arising from blood flow and responds to altered shear by activation of NADPH (NOX2) to generate reactive oxygen species (ROS). This review describes the pathway for NOX2 activation and the downstream ROS-mediated signaling events on the basis of studies of isolated lungs and flow-adapted endothelial cells in vitro that are subjected to acute flow cessation (ischemia). Altered mechanical stress is detected by a cell-associated complex involving caveolae and other membrane proteins that results in endothelial cell membrane depolarization and then the activation of specific kinases that lead to the assembly of NOX2 components. ROS generated by this enzyme amplify the mechanosignal within the endothelial cell to regulate activation and/or synthesis of proteins that participate in cell growth, proliferation, differentiation, apoptosis, and vascular remodeling. These responses indicate an important role for NOX2-derived ROS associated with mechanotransduction in promoting vascular homeostasis.

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

“…Mechanotransduction is a process through which cells sense altered physical forces and convert them into biological signals (18). The response of endothelium to dynamic fluid shear stress is one example of mechanotransduction (25,78).…”

“…The response of endothelium to dynamic fluid shear stress is one example of mechanotransduction (25,78). Interestingly, the activities of many ion channels could be modulated in response to altered shear stress in this process (18,27,131). These channels sense mechanical forces and transduce them into electrical/biochemical signals.…”

The serpentine path to a novel mechanism-based inhibitor of acute inflammatory lung injury

“…O 2 ·Ϫ serves as a signal for endothelial cell proliferation, perhaps, teleologically, representing an attempt to restore pulmonary blood flow (62). Thus ROS mediatedsignaling appears to play a key role in the physiological response to altered shear stress associated with lung ischemia (10). But before further consideration of these latter observations, I need to digress to discuss our studies of lung surfactant phospholipid metabolism.…”

Effects of shear stresses and antioxidant concentrations on the production of reactive oxygen species in lung cancer cells

“…ROS, mainly produced in the mitochondrion during oxidative phosphorylation, 1 are natural byproducts of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. [2][3][4] Normally, the amount of ROS is maintained at the basal and nontoxic level via the regulation of the antioxidant defense system of cells. Excess ROS, the so-called oxidative stress, can lead to cell damage and apoptosis [5][6][7][8] and is found to be related to the development of certain diseases such as Parkinson's disease, [9][10][11][12] Alzheimer's disease, [13][14][15] atherosclerosis, [16][17][18] and heart failure.…”

“…[31][32][33] Further understanding of the underlying mechanism of how ROS affect tumor growth and metastasis will definitely help in the development of ROS-mediated anticancer therapies. Some possible reasons for the excess production of ROS in cells include (1) short-term increase in ROS after exhaustive exercise, [34][35][36][37] (2) exogenous ROS sources such as UV, ionizing radiation, pollutants, environmental toxins, etc., and a) Author to whom correspondence should be addressed. Electronic mail: 089957@mail.fju.edu.tw 1932-1058/2013/7(6)/064108/12/$30.00 V C 2013 AIP Publishing LLC 7, 064108-1 (3) diseases such as hypertension, 38 cardiac disease, and diabetes.…”