H2O2-induced proliferation of primary alveolar epithelial cells is mediated by MAP kinases.
Exposure to supraphysiological oxygen concentrations during ventilatory oxygen therapy often causes tissue damage. Alveolar type II (AT II) cells are a major target for oxidant injury, and their ability to proliferate plays a critical role during the repair phase following injury. We hypothesized that reactive oxygen species (ROS), which are produced during hyperoxia, not only cause cellular damage, but may also play a role in the repair process by promoting AT II cell proliferation. We have tested the ability of ROS to induce proliferation in primary cultures of AT II cells by using a wide range of chronic and acute hydrogen peroxide (H2O2) exposures to mimic different types of oxidative stress. We found that chronic exposure to an extracellular flux of 10 microM H2O2/h can significantly increase the intracellular concentration of oxidants, DNA synthesis, and cell proliferation. H2O2-induced AT II cell proliferation was preceded by activation of the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). Inhibition of ERK and p38 activation prevented H2O2-induced proliferation. These results show that changes in intracellular oxidant concentrations can modulate downstream signaling pathways controlling AT II cell proliferation. This mechanism could be important in the repair process following hyperoxia-induced injury.
Sigaud
Samuel
S
Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
Evelson
Pablo
P
González-Flecha
Beatriz
B
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016877:Oxidants; D017382:Reactive Oxygen Species; D004247:DNA; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; C020667:glutathione oxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen