Liposome-Encapsulated Hemoglobin Accelerates Bronchial Healing After Pneumonectomy in the Rat With or Without Preoperative Radiotherapy

Abstract

Liposome-encapsulated hemoglobin (LEH) has been reported to accelerate wound healing in the stomach and skin in an experimental setting. LEH was tested in bronchial anastomotic healing after radiation and pneumonectomy in the rat. Sprague-Dawley rats (n = 61) received preoperative radiation (20 Gy) to the chest and underwent left pneumonectomy with bronchial stump closure using the Sweet method 4 days later, when they were randomized to receive intravenous infusion of LEH with high O2 affinity (P50 O2 = 17 mm Hg, 10 mL/kg, n = 32) or saline (n = 29). Additional rats (n = 18) were treated in the same way without preoperative radiation. Bronchial anastomotic healing was evaluated 2 days after surgery by determining the bursting pressure and infiltration of neutrophils, monocytes, and macrophages. Bronchial bursting pressure was elevated in the rats receiving LEH both in the unirradiated group (LEH 212 ± 78 vs. saline 135 ± 63 mm Hg, P < 0.05) and in rats with preoperative radiation (LEH 162 ± 48 vs. saline 116 ± 56 mm Hg, P < 0.01). Moreover, the percentage of rats with bursting pressure <100 mm Hg tended to be smaller in the unirradiated group (LEH 1/9 [11.1%] vs. saline 4/9 [44.4%], NS) and was significantly reduced in irradiated animals (LEH 3/32 [9.4%] vs. saline 11/29 [38%], P < 0.05). There were no morphological differences except for macrophage infiltration to the anastomotic area, which was significantly prominent in the LEH-treated rats (P < 0.05) regardless of the presence or absence of preoperative irradiation (IR). The results suggest that LEH with high O2 affinity may improve mechanical strength and morphological findings in bronchial anastomosis in rats regardless of the presence or absence of preoperative IR. The irradiated rats later treated with LEH had equivalent or better bronchial healing than that of saline-treated naïve animals undergoing pneumonectomy alone.

Artificial Oxygen Carrier to Regulate Hypoxic Signal Transduction

“…It has been our consistent observation that liposome‐encapsulated hemoglobin (LEH), specifically with high O 2 affinity ( h ‐LEH, P 50 O 2 = 8–17 mm Hg), has been associated with suppressed inflammation to promote wound healing , reduce damage after ischemia/reperfusion , and enhance antitumor therapies . Whereas LEH with low O 2 affinity ( l ‐LEH, P 50 O 2 = 40–50 mm Hg) was able to maintain O 2 delivery as a whole in rabbits under hemorrhagic shock, it was not associated with improved peripheral perfusion or extended survival .…”

“…Thus, a more convincing argument might be that improvements in the microenvironment may foster and accelerate the process of regeneration after surgery , trauma , hemorrhage , or ischemia/reperfusion injury . As speculated in each of these experimental studies, the wound healing process is a sum of various factors; while the surgically obtained strength (Fig.…”

“…Cellular response to innate immunity , as well as nuclear factor kappa‐B, has also been interrelated with HIF‐1α to control the microenvironment against hypoxia, infection, and inflammation . Observations compatible with this theory include milder wound adhesion , decreased inflammatory cell infiltration , reduced proinflammatory cytokines , and a widened therapeutic window late after ischemic events (11) involving reperfusion rather than permanent ischemia. The extended dose‐response relationship (minimal effective dose as little as 0.4 mL/kg []), and plateaued efficacy at the other end suggests that aerobic energy generation per se was not the sole mechanism(s) behind the benefits so far accredited to AOC or its O 2 delivery.…”

“…As speculated in each of these experimental studies, the wound healing process is a sum of various factors; while the surgically obtained strength (Fig. ) will only decrease, the healing process will increase the anastomotic strength; the sum of them represents the total mechanical strength of the wound, which was measured as the surrogate of tissue healing . While clinical gastrointestinal leakage or bronchial dehiscence usually occurs 1–2 weeks after surgery when the total mechanical strength passes under the threshold, experimental animals showed the lowest bursting pressure at 2 days in the stomach as well as with bronchial surgery .…”

“…) will only decrease, the healing process will increase the anastomotic strength; the sum of them represents the total mechanical strength of the wound, which was measured as the surrogate of tissue healing . While clinical gastrointestinal leakage or bronchial dehiscence usually occurs 1–2 weeks after surgery when the total mechanical strength passes under the threshold, experimental animals showed the lowest bursting pressure at 2 days in the stomach as well as with bronchial surgery . Such accelerated healing in animals or delayed dehiscence in humans may be accounted for by the difference in body size ; the unit of time after surgery/trauma (Fig.…”