Patent Vasculature Research Articles

A Case of Drug-Induced Hepatitis from Methyl 1-P, an Anabolic Androgenic Steroid

Purpose: To illustrate the hepatotoxic effect of a commonly available anabolic steroid and the management of the resulting hepatitis. Methods: Case Description: A 28 year-old Caucasian male presented with nausea, vomiting, pruritus and jaundice following flu-like symptoms. Four to five weeks prior to the hospitalization he had consumed methyl 1-P (an anabolic steroid) for a period of 2 months to enhance his muscle mass. He did not take any other medications or drink alcohol. His physical examination showed scleral icterus, yellowish skin and hepatomegaly. The liver profiles showed a total bilirubin of 58 mg/dl with conjugated bilirubin of 45 mg/dl, alkaline phosphatase 238 U/L, AST 48 U/L, ALT 62 U/L and INR 1.0. Viral serologies including hepatitis A, B, C, E, CMV, EBV and HSV were negative. The autoimmune markers, iron studies and markers of Wilson's disease were all normal. His creatinine was 2.5 mg/dl. Ultrasound and MRI/MRCP imaging showed an enlarged liver with a normal biliary tree and patent hepatic vasculature. Liver biopsy revealed centrilobular and canalicular cholestasis without showing bile duct injury or portal/lobular inflammation consistent with drug induced cholestatic hepatitis. A kidney biopsy showed acute interstitial nephritis with tubular injury and bile casts. Results: The patient was managed with ursodeoxycholic acid, hydroxazine and Benadryl with satisfactory symptom relief. One week following discharge his total bilirubin decreased to 34 mg/dl and his creatinine level was improving Conclusion: A variety of side effects including hepatoxicity have been described with the use of anabolic androgenic steroids. However to our knowledge, Methyl 1-P induced cholestasis has not been reported in the literature. Methyl 1-P contains two steroids, progestin and a second steroid that resembles androstenedione. Renal failure due to anabolic steroids is rare but has been reported. Despite FDA regulations against possession, production and marketing of anabolic steroids, these drugs are freely available as dietary supplements. Increased awareness among consumers and the medical community are required regarding the potential lethal complications of anabolic steroid including hepatotoxicity. Obtaining a good drug history, early diagnosis and prompt discontinuation of the offending drug can lead to gradual but complete recovery over a period of several months.

“Splenic artery steal syndrome” is a misnomer: The cause is portal hyperperfusion, not arterial siphon

Splenic artery embolization (SAE) improves hepatic artery (HA) flow in liver transplant (OLT) recipients with so-called splenic artery steal syndrome. We propose that SAE actually improves HA flow by reducing the HA buffer response (HABR). Patient 1: On postoperative day (POD) 1, Doppler ultrasonography (US) showed patent vasculature with HA resistive index (RI) of 0.8. On POD 4, aminotransferases rose dramatically; his RI was 1.0 with no diastolic flow. Octreotide was begun, but on POD 5 US showed reverse diastolic HA flow with no signal in distal HA branches. After SAE, US showed markedly improved flow, RI was 0.6, diastolic flow in the main artery, and complete visualization of all distal branches. By POD 6, liver function had normalized. RI in the main HA is 0.76 at 2 months postsurgery. Patient 2: On POD 1, RI was 1.0. US showed worsening intrahepatic signal, with no signal in the intrahepatic branches and reversed diastolic flow despite good graft function. On POD 7, SAE improved the intrahepatic waveform and RI (from 1.0 to 0.72). Patient 3: Intraoperative reverse diastolic arterial flow persisted on PODs 1, 2, and 3, with progressive loss of US signal in peripheral HA branches. SAE on POD 4 improved the RI (0.86) and peripheral arterial branch signals. Patient 4: US on POD 1 showed good HA flow with a normal RI (0.7). A sudden waveform change on POD 2 with increasing RI (0.83) prompted SAE, after which the wave form normalized, with reconstitution of a normal diastolic flow (RI 0.68). In conclusion, these reports confirm the usefulness of SAE for poor HA flow but suggest that inflow steal was not the problem. Rather than producing an increase in arterial inflow, SAE worked by reducing portal flow and HABR, thereby reducing end-organ outflow resistance. Evidence of this effect is the marked reduction of the RI after the SAE to 0.6, 0.72, 0.86, and 0.68, in patients 1-4, respectively. SAE reduces excessive portal vein flow and thereby ameliorates an overactive HABR that can cause graft dysfunction and ultimately HA thrombosis.

In VivoPulmonary Tissue Engineering: Contribution of Donor-Derived Endothelial Cells to Construct Vascularization*

Intrapulmonary engraftment of engineered lung tissues could provide a potential therapeutic approach for the treatment of pediatric and adult pulmonary diseases. In working toward this goal, we report here on in vivo generation of vascularized pulmonary tissue constructs utilizing the subcutaneous Matrigel plug model. Mixed populations of murine fetal pulmonary cells (FPCs) containing epithelial, mesenchymal, and endothelial cells (ECs) were isolated from the lungs of embryonic day 17.5 fetuses. FPCs were admixed to Matrigel and injected subcutaneously into the anterior abdominal wall of adult C57/BL6 mice to facilitate in vivo pulmonary tissue construct formation. Vascularization was enhanced by placing fibroblast growth factor 2 (FGF2)-loaded polyvinyl sponges into the hydrogel. After 1 week, routine histology and immunohistochemical staining for donor-derived epithelial cells and ECs as well as analysis of patent vasculature in the constructs following tail vein injection of fluorescein isothiocyanate-conjugated dextran were performed. In the Matrigel-only controls, some level of host infiltrate, but no measurable vascularization, was detected. In the presence of FPCs, the constructs contained ductal epithelial structures and patent vasculature. In the absence of FPCs, exogenous FGF2 induced the formation of numerous patent blood vessels throughout the entire constructs; in combination with FPCs, it resulted in enhanced capillary density and abundant interfacing between developing epithelial and vascular structures. The significant findings of this study are that distal pulmonary epithelial differentiation (as assessed by the expression of prosurfactant protein C) can be maintained in vivo and that donor-derived ECs contribute to the formation of patent vessels that interface tightly with ductal epithelial structures.

A Self-Assembled Fibroblast-Endothelial Cell Co-Culture System That Supports in vitro Vasculogenesis by both Human Umbilical Vein Endothelial Cells and Human Dermal Microvascular Endothelial Cells

The construction of vascularized connective tissues is an important goal in tissue engineering in that the presence of a patent bio-engineered vasculature should facilitate vascularization of an implant. Fibroblasts play an essential role in the angiogenic process through their production of extracellular matrix molecules and through their release of essential growth factors. Therefore, the aim of this study is to develop a thin 3-dimensional model in which fibroblasts support endothelial cells in the formation of tube-like structures. Macro- and microvascular endothelial cells were seeded onto confluent lawns of human fibroblasts and were cultured in the presence of high levels of ascorbate 2-phosphate to create a tissue-like structure in which endothelial cell organized into tube-like structures. The process was visualized in the culture dish through labeling of cells with a long-lasting fluorescent vital dye. Intact sheet-like structures were created in which endothelial cell tube-like structures were encased by fibroblasts and were surrounded by a basement membrane. These structures appeared to contain a lumen and remained stable for up to 5 weeks in culture. This culture system provides an in vitro method to study fibroblast-endothelial cell interactions and to study the effects of pro- and anti-angiogenic factors on endothelial cell differentiation. This system also provides an experimental basis for developing vascularized tissue-engineered connective tissue.

Pulp nonfiction: microscopic anatomy of the digital pulp space.

The volar pad of the fingertip provides a very stable yet sensitive surface that gives the hand the ability to pinch and grasp. The focus of this study was to advance understanding of the anatomical features of the digital pulp space. The unusual features of the fingertip pulp space include prominent collagen fiber cords and a branching continuous fine vasculature. Prominent collagen fiber cords radiating out from beneath the epidermal basement membrane are like the cords of a parachute, which directly attach to the periosteum of the distal phalanx. Those collagen fiber cords are responsible for the firm attachment of the fingertip to the distal phalanx. There is a fine patent vasculature within the pulp space. Also contained in the capsule are numerous lobules of fat, which contribute to some elasticity of the fingertip. Principles of treatment for injuries or infections of the digital pulp should attempt to preserve this anatomical construct so that the firmness and vascular supply of the fingertip are maintained and not disrupted.

Platelet-derived growth factor BB induces functional vascular anastomoses in vivo.

Neovascularization that generates collateral blood flow can limit the extent of tissue damage after acute ischemia caused by occlusion of the primary blood supply. The neovascular response stimulated by the BB homodimeric form of recombinant platelet-derived growth factor (PDGF-BB) was evaluated for its capacity to protect tissue from necrosis in a rat skin flap model of acutely induced ischemia. Complete survival of the tissue ensued, when the original nutritive blood supply was occluded, as early as 5 days after local PDGF-BB application, and the presence of a patent vasculature was evident compared to control flaps. To further evaluate the vascular regenerative response, PDGF-BB was injected into the muscle/connective tissue bed between the separated ends of a divided femoral artery in rats. A patent new vessel that functionally reconnected the ends of the divided artery within the original 3- to 4-mm gap was regenerated 3 weeks later in all PDGF-BB-treated limbs. In contrast, none of the paired control limbs, which received vehicle with an inactive variant of PDGF-BB, had vessel regrowth (P < 0.001). The absence of a sustained inflammatory response and granulation tissue suggests locally delivered PDGF-BB may directly stimulate the angiogenic phenotype in endothelial cells. These findings indicate that PDGF-BB can generate functional new blood vessels and nonsurgically anastomose severed vessels in vivo. This study supports the possibility of a therapeutic modality for the salvage of ischemic tissue through exogenous cytokine-induced vascular reconnection.

Mechanisms of thrombus formation and lysis

Maintenance of a patent vasculature is critical to provide nutrient blood flow to dependent tissues. This is normally facilitated by vessels composed of actively nonthrombogenic endothelium and blood that contains both nonactivated platelets and inactive coagulation proenzymes. Following vessel injury, active hemostasis results from vasoconstriction, adherence and aggregation of activated platelets, and coagulation enzyme activation. The resulting thrombus contains a mixture of blood cells and the insoluble product of coagulation, fibrin, which further stimulates the activation of another blood enzyme system known as the fibrinolytic system. This results in the conversion by plasminogen activators of the circulating plasma proenzyme plasminogen into the active fibrinolytic enzyme plasmin, which dissolves the clot into degradation products. Vascular patency ultimately is restored and healing is thus facilitated. The hemostatic system is highly regulated by a variety of processes. Derangement of regulation can lead to disease manifesting either as thrombosis or hemorrhage. Furthermore, improved understanding of the molecular interactions involved in these processes has led to design of newer therapeutic interventions targeted toward amelioration of the sequelae of thromboembolic disease.

Enzymatic frostbite eschar debridement by bromelain

Bromelain is a plant proteinase derived from the stem of the pineapple plant that has been used successfully to debride the eschar from third-degree burn injuries. Its applicability to frostbite eschar removal was extrapolated and investigated. Third-degree frostbite lesions were produced on swine using supercooled air as the freezing media, and the resulting eschars were treated with a bromelain preparation. In the initial trial, no debridement other than that of the superficial layers of the eschar was noted. The experiment then was repeated with the introduction of third-degree burn injuries as a control to validate the efficacy of the enzyme preparation. Although the burn injuries debrided to a graftable bed after two applications of the enzyme, the frostbite injuries remained unaffected. It was concluded that the patent vasculature, resulting tissue edema, and lack of coagulation of proteins found in the freeze injury are sufficient to inactivate the bromelain enzyme before tissue digestion and dissection can be effected.

Enzymatic frostbite eschar debridement by bromelain

Bromelain is a plant proteinase derived from the stem of the pineapple plant that has been used successfully to debride the eschar from third-degree burn injuries. Its applicability to frostbite eschar removal was extrapolated and investigated. Third-degree frostbite lesions were produced on swine using supercooled air as the freezing media, and the resulting eschars were treated with a bromelain preparation. In the initial trial, no debridement other than that of the superficial layers of the eschar was noted. The experiment then was repeated with the introduction of third-degree burn injuries as a control to validate the efficacy of the enzyme preparation. Although the burn injuries debrided to a graftable bed after two applications of the enzyme, the frostbite injuries remained unaffected. It was concluded that the patent vasculature, resulting tissue edema, and lack of coagulation of proteins found in the freeze injury are sufficient to inactivate the bromelain enzyme before tissue digestion and dissection can be effected.

Dermal vascular patterns in response to burn or freeze injury in rats

Full thickness injury of rat skin by burning results in wound healing with contraction whereas wounds of similar area and depth caused by freezing heal without contracting. Burns cause cell death and denaturation of the connective tissue matrix; freezing causes cell death, but the matrix is not immediately denatured and appears to maintain its integrity during the initial phases of repair. Differences in vascular perfusion within and surrounding the site of burn and freeze injury are described in the present study. During the first 2 hr after burning, arteriograms and Microfil latex vascular casts showed reduced, but existent perfusion at the injury site; in contrast, the site of freezing showed little perfusion. At 4 to 5 hr following injury, this pattern had reversed. There was loss of perfusion in the burn injury site and reappearance of perfusion in the frozen site. At 24 hr, the burned site was nearly avascular and surrounded by an area of vasodilatation. The frozen site had a patent vasculature within the dermis and little vasodilatation in the surrounding area. The persistent perfusion in the frozen dermis was presumably through vascular channels which were dead, but not occluded. We suspect that factors released from the burned matrix account for some of these differences in pattern of vascular perfusion.

The no-reflow phenomenon after canine renal preservation with medium 199

Twenty-four-hr renal preservation at hypothermic temperatures with pulsatile flow using either Medium 199 or a cryoprecipitate of plasma maintained a patent microcirculation prior to reestablishing blood flow. However, failed reflow of blood, the no-reflow phenomenon, occurred in kidneys preserved with Medium 199 within 4 hr after reimplantation into the host animal, as determined by the intra-arterial injection of carbon. The site of vascular obstruction in the renal microcirculation was documented to be within the glomerulus or in the preglomerular afferent arteriole. Renal preservation using a cryoprecipitate of plasma maintained a patent intrarenal vasculature after restoration of blood flow providing normal or near normal function.