Attenuating ischemia-reperfusion injury with polymerized albumin

Abstract

Ischemia-reperfusion injury increased vascular permeability, resulting in fluid extravasation from the intravascular compartment into the tissue space. Fluid and small protein extravasation lead to increased interstitial fluid pressure and capillary collapse, impairing capillary exchange. Polymerized human serum albumin (PolyHSA) has an increased molecular weight (MW) compared with unpolymerized human serum albumin (HSA) and can improve intravascular fluid retention and recovery from ischemia-reperfusion injury. To test the hypothesis that polymerization of HSA can improve recovery from ischemia-reperfusion injury, we studied how exchange transfusion of 20% of the blood volume with HSA or PolyHSA immediately before reperfusion can affect local ischemic tissue microhemodynamics, vascular integrity, and tissue viability in a hamster dorsal window chamber model. Microvascular flow and functional capillary density were maintained in animals exchanged with PolyHSA compared with HSA. Likewise, exchange transfusion with PolyHSA preserved vascular permeability measured with extravasation of fluorescently labeled dextran. The intravascular retention time of the exchanged PolyHSA was significantly longer compared with the intravascular retention time of HSA. Lastly, the viability of tissue subjected to ischemia-reperfusion injury increased in animals exchanged with PolyHSA compared with HSA. Therefore maintenance of microvascular perfusion, improvement in vascular integrity, and reduction in tissue damage resulting from reperfusion with PolyHSA suggest that PolyHSA is a promising fluid therapy to improve outcomes of ischemia-reperfusion injury.NEW & NOTEWORTHY Polymerized human serum albumin reduced reperfusion injury and preservers microvascular hemodynamics. Polymerized human serum albumin reduces fluid extravasation and prevents fluid extravasation. Consequently, the tissue viability of ischemic tissue is preserved by polymerized human serum.

Keywords: hemodynamics; ischemia-reperfusion injury; plasma substitute; trauma; vascular integrity.

Graphical abstract

Figure 1.

Ischemia model and illustration of groups included in the study. Animals received an exchange transfusion of 20% of the estimated blood volume using HSA (10 g/dL) or PolyHSA (10 g/dL) before the release of the ischemia. Alternatively, a third group received no hemodilution. HSA, human serum albumin; Poly HSA, polymerized HSA.

Figure 2.

Mean arterial pressure (MAP; A) and heart rate (HR; B) measured throughout ischemia followed by reperfusion with no exchange transfusion (control), exchange transfusion of HSA, or exchange transfusion of PolyHSA. Symbols indicate significance levels *P < 0.05 and **P < 0.01 between treatment groups at the same time point; n = 8 animals/group. HSA, human serum albumin; Poly HSA, polymerized HSA.

Figure 3.

Microhemodynamic diameters and blood flow relative to baseline measured throughout ischemia followed by reperfusion with no exchange transfusion (control), exchange transfusion of HSA, or exchange transfusion of PolyHSA. Symbols indicate significance levels *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 between treatment groups at the same time point. †P < 0.05 compared with baseline conditions; n = 12 vessels/group. BL, baseline; HSA, human serum albumin; Poly HSA, polymerized HSA.

Figure 4.

Functional capillary density (FCD; A) and immobilized leukocytes (B) throughout ischemia followed by reperfusion with no exchange transfusion (control), exchange transfusion of HSA, or exchange transfusion of PolyHSA. Symbols indicate significance levels *P < 0.05, **P < 0.01, and ***P < 0.001 between treatment groups at the same time point. †P < 0.05 compared to baseline conditions; n = 6 animals/group. BL, baseline; HSA, human serum albumin; Poly HSA, polymerized HSA.

Figure 5.

Vascular permeability of animals postischemia/reperfusion injury (A) and extravasation of HSA and PolyHSA post-ischemia/reperfusion injury (B). Symbols indicate significance levels *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 between treatment groups at the same time point. †P < 0.05 compared to baseline conditions; n = 6 animals/group. BL, baseline; EV, extravascular; HSA, human serum albumin; IV, intravascular; Poly HSA, polymerized HSA.

Figure 6.

Number of apoptotic and necrotic cells. A: number of annexin V positive and propidium iodine (PI) positive stained cells. B: number of necrotic (PI⁺/Annexin V⁻), late apoptotic (PI⁺/Annexin V⁺), and early apoptotic (PI⁻/Annexin V⁺) cells for each treatment group after 24 hours of reperfusion. †P < 0.05 compared with sham, ‡P < 0.05 compared with animals that received no exchange transfusion, §P < 0.05 compared with animals that were administered has; n = 6 animals/group. HSA, human serum albumin; Poly HSA, polymerized HSA.