Isoproterenol attenuates high vascular pressure-induced permeability increases in isolated rat lungs

Abstract

To separate the contributions of cellular and basement membrane components of the alveolar capillary barrier to the increased microvascular permeability induced by high pulmonary venous pressures (Ppv), we subjected isolated rat lungs to increases in Ppv, which increased capillary filtration coefficient (Kfc) without significant hemorrhage (31 cmH2O) and with obvious extravasation of red blood cells (43 cmH2O). Isoproterenol (20 microM) was infused in one group (Iso) to identify a reversible cellular component of injury, and residual blood volumes were measured to assess extravasation of red blood cells through ruptured basement membranes. In untreated lungs (High Ppv group), Kfc increased 6.2 +/- 1.3 and 38.3 +/- 15.2 times baseline during the 31 and 43 cmH2O Ppv states. In Iso lungs, Kfc was 36.2% (P < 0.05) and 64.3% of that in the High Ppv group at these Ppv states. Residual blood volumes calculated from tissue hemoglobin contents were significantly increased by 53-66% in the high Ppv groups, compared with low vascular pressure controls, but there was no significant difference between High Ppv and Iso groups. Thus isoproterenol significantly attenuated vascular pressure-induced Kfc increases at moderate Ppv, possibly because of an endothelial effect, but it did not affect red cell extravasation at higher vascular pressures.

High Vascular Pressure–Induced Lung Injury Requires P450 Epoxygenase–Dependent Activation of TRPV4

“…In the current study, we found that the increase in V af /V as observed in wild-type lung after HiPv was absent in TRPV4 2/2 lung. These data confirm previous reports that HiPv targets the alveolar septal compartment, evoking disruption of alveolar septal capillaries and alveolar flooding (5,(22)(23)(24)31), and suggest that this is due to HiPv-induced activation of TRPV4.…”

“…*P , 0.05 versus BL; # P , 0.05 versus wild-type control group. when Pv exceeds approximately 30 to 50 cm H 2 O in mammalian lung (2)(3)(4)(20)(21)(22). Using vascular corrosion casting with low viscosity prepolymerized methyl methacrylate, we have shown that the alveolar septal barrier is the site of leak in the pulmonary circulation when HiPv increases permeability (23).…”

“…However, since the early literature provided clear evidence for mechanical disruption of the septal barrier with HiPv, the notion that mechanical stress in lung may act in part by initiating intracellular signaling pathways which impact barrier function has only recently been investigated. Parker and Ivey (22) found that isoproterenol could protect against HiPv-induced acute lung injury, suggesting active regulation of barrier integrity could offset stresses induced by mechanical perturbation. Subsequently, they reported that another type of mechanically induced lung injury, that secondary to over-ventilation, increased K f in a Ca 21 entry-dependent fashion (10).…”

Pressure is proinflammatory in lung venular capillaries

“…A large number of in vitro studies indicate that mechanically stretched endothelial cells evoke a variety of potentially proinflammatory responses, including cytokine secretion (1), superoxide production (2), secretion of monocyte chemotactic protein (3) and endothelin (4), increases of the cytosolic Ca 2+ concentration ([Ca 2+ ] i ) (5,6), and activation of tyrosine kinases (7) and transcription factors (8). Such responses might underlie vascular pathology such as inflammation (9) or permeability increase (10) in pressure-induced lung disease.…”

“…However, recent reports indicate that the lung vascular response to high pressure may be more complex. Increase of P LA to 20-50 cmH 2 O increases the lung capillary filtration coefficient (10,55) and enhances transvascular protein flow (56). Higher increases of the pressure (>50 cmH 2 O) cause capillary breaks (57,58) and more intense permeability increases (59).…”