Integrin {alpha}v{beta}3 acts downstream of insulin in normalization of interstitial fluid pressure in sepsis and in cell-mediated collagen gel contraction

1 Department of Biomedicine, University of Bergen, Bergen, Norway; 2 Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; and 3 Department of Anesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway Submitted 15 February 2008 ; accepted in final form 2 June 2008 The administration of insulin is recommended to patients with severe sepsis and hyperglycemia. Previously, we demonstrated that insulin may have direct anti-inflammatory properties and counteracted fluid losses from the circulation by normalizing the interstitial fluid pressure (P IF ). P IF is one of the Starling forces determining fluid flux over the capillary wall, and a lowered P IF is one of the driving forces in early edema formation in inflammatory reactions. Here we demonstrate that insulin restores a lipopolysaccharide (LPS)-lowered P IF via a mechanism involving integrin v β 3 . In C57 black mice ( n = 6), LPS lowered P IF from –0.2 ± 0.2 to –1.6 ± 0.3 ( P < 0.05) and after insulin averaged –0.8 ± 0.2 mmHg ( P = 0.098 compared with after LPS). Corresponding values in wild-type BALB/c mice ( n = 5) were –0.8 ± 0.1, –2.1 ± 0.3 ( P < 0.05), and –0.8 ± 0.3 mmHg ( P < 0.05 compared with LPS) after insulin administration. In BALB/c integrin β 3 -deficient (β 3 –/– ) mice ( n = 6), LPS lowered P IF from –0.1 ± 0.2 to –1.5 ± 0.3 mmHg ( P < 0.05). Insulin did not, however, restore P IF in these mice (averaged –1.7 ± 0.3 mmHg after insulin administration). Cell-mediated collagen gel contraction can serve as an in vitro model for in vivo measurements of P IF . Insulin induced v β 3 -integrin-dependent collagen gel contraction mediated by C2C12 cells. Our findings suggest a beneficiary effect of insulin for patients with sepsis with regard to the fluid balance, and this effect may in part be due to a normalization of P IF by a mechanism involving the integrin v β 3 . glucose-insulin-potassium treatment; tissue fluid balance; inflammation Address for reprint requests and other correspondence: Ø. S. Svendsen, Dept. of Biomedicine, Univ. of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway (e-mail: oyvind.svendsen{at}biomed.uib.no )