Impact of cell swelling on proliferative signal transduction in the liver

Cellular swelling has emerged as an important initiator of metabolic and pr oliferative changes in various cells. Because of the unique regenerative ca pacity of the adult liver, researchers have delineated key intracellular si gnals that are activated following mitogens, injury, and partial hepatectom y. Although hepatocellular swelling is commonly observed following these re generative stimuli, only recently has the relationship between cell volume increase and proliferative activity been investigated; to date, the data im plicating cell volume increase with hepatocyte regeneration has been mostly indirect. Hepatocyte swelling has been demonstrated in various clinical sc enarios from sepsis, hepatic resection, ischemia-reperfusion injury, glucoc orticoid excess, and hyperinsulinemia. Using various in vivo and in vitro m odels of hepatocyte swelling, particularly hypo-osmotic stress, investigato rs have demonstrated changes in cellular structure: (1) cell membrane stret ch, (2) cytoskeletal microtubule and microfilament reorganization, and (3) alterations in cytoskeletal-membrane complexes. Similar studies have demons trated a causal relationship between cell volume increase and intracellular signals: (1) activation of cytoplasmic signaling cascades such as MAPKs, P I-3-K, and PKC, (2) activation of proliferative transcription factors NF-ka ppaB, AP-1, STATs, C/EBPs, and (3) transcription of metabolic and immediate early genes of regeneration. Through mechanotransduction, or the translati on of physical changes to chemical signals, cell volume is a potent effecto r of these signaling events. Growing evidence demonstrates a link between t hese physical and chemical changes in the swelling-mediated growth in the l iver. J. Cell. Biochem. 83: 56-69, 2001. (C) 2001 Wiley-Liss, Inc.