Jeffrey R. Scott

Cell surface biliverdin reductase mediates biliverdin-induced anti-inflammatory effects via phosphatidylinositol 3-kinase and Akt.

Biliverdin reductase A (BVR) catalyzes the reduction of biliverdin (BV) to bilirubin (BR) in all cells. Others and we have shown that biliverdin is a potent anti-inflammatory molecule, however, the mechanism by which BV exerts its protective effects is unclear. We describe and elucidate a novel finding demonstrating that BVR is expressed on the external plasma membrane of macrophages (and other cells) where it quickly converts BV to BR. The enzymatic conversion of BV to BR on the surface by BVR initiates a signaling cascade through tyrosine phosphorylation of BVR on the cytoplasmic tail. Phosphorylated BVR in turn binds to the p85α subunit of phosphatidylinositol 3-kinase and activates downstream signaling to Akt. Using bacterial endotoxin (lipopolysaccharide) to initiate an inflammatory response in macrophages, we find a rapid increase in BVR surface expression. One of the mechanisms by which BV mediates its protective effects in response to lipopolysaccharide is through enhanced production of interleukin-10 (IL-10) the prototypical anti-inflammatory cytokine. IL-10 regulation is dependent in part on the activation of Akt. The effects of BV on IL-10 expression are lost with blockade of Akt. Inhibition of surface BVR with RNA interference attenuates BV-induced Akt signaling and IL-10 expression and in vivo negates the cytoprotective effects of BV in models of shock and acute hepatitis. Collectively, our findings elucidate a potentially important new molecular mechanism by which BV, through the enzymatic activity and phosphorylation of surface BVR (BVR)surf modulates the inflammatory response.

Inhalation of carbon monoxide prevents liver injury and inflammation following hind limb ischemia/reperfusion

The induction of heme oxygenase (HO), the rate limiting enzyme in the conversion of heme into carbon monoxide (CO) and biliverdin, limits liver injury following remote trauma such as hind limb ischemia/reperfusion (I/R). Using intravital video microscopy, we tested the hypothesis that inhaled CO (250 ppm) would mimic HO‐derived liver protection. Hind limb I/R significantly decreased sinusoidal diameter and volumetric flow, increased leukocyte accumulation within sinusoids, increased leukocyte rolling and adhesion within postsinusoidal venules, and significantly increased hepatocyte injury compared with naïve animals. Inhalation of CO alone did not alter any microcirculatory or inflammatory parameters. Inhalation of CO following I/R restored volumetric flow, decreased stationary leukocytes within sinusoids, decreased leukocyte rolling and adhesion within postsinusoidal venules, and significantly reduced hepatocellular injury following hind limb I/R. HO inhibition did not alter microcirculatory parameters in naïve mice, but did increase inflammation, as well as increase hepatocyte injury following hind limb I/R. Inhalation of CO during HO inhibition significantly reduced such microcirculatory deficits, hepatic inflammation, and injury in response to hind limb I/R. In conclusion, these results suggest that HO‐derived hepatic protection is mediated by CO, and inhalation of low concentrations of CO may represent a novel therapeutic approach to prevent remote organ injury during systemic inflammatory response syndrome, or SIRS.

Analysis of acellular dermal matrix integration and revascularization following tissue expander breast reconstruction in a clinically relevant large-animal model.

Background: Postmastectomy breast reconstruction remains one of the most frequently performed plastic surgery procedures in the United States. Acellular dermal matrix has been used extensively in expander-implant breast reconstruction and therefore is an appropriate material to be used to develop a clinically relevant animal model of breast reconstruction. Methods: The study population consisted of 18 female Yorkshire pigs, which were assigned randomly to bilateral expander breast reconstruction with either AlloMax Surgical Graft or AlloDerm Regenerative Tissue Matrix (n = 9 per group). Each group was further randomized to 4-, 8-, or 12-week time points (n = 3), to evaluate integration and neovascularization by means of microcirculatory and histologic techniques. Results: Microcirculatory analysis revealed early acellular dermal matrix angiogenesis at 4 weeks on the skin flap surfaces only, and well-formed vasculature on both acellular dermal matrix surfaces at 8 weeks. Both surfaces were vascularized and exhibited detectable flow at 12 weeks after implantation. Progressive acellular dermal matrix angiogenesis was also histologically observed over time by means of hematoxylin and eosin–stained slides, as indicated by direct vascular identification/scoring at 4, 8, and 12 weeks. Conclusions: The authors have developed a clinically relevant large-animal model of breast reconstruction using acellular dermal matrix. The acellular dermal matrix inflammatory, neovascularization, and tissue integration response should be evaluated in an in vivo setting that accurately simulates the anatomy, biomaterials, surgical techniques, and timeframes encountered in human postmastectomy breast reconstruction to appropriately predict clinical performance. Neovascularization of the acellular dermal matrix with detectable blood flow took place after postimplantation week 8, a much slower process than previously reported in models not clinically relevant to acellular dermal matrix–assisted tissue expander breast reconstruction.

Characterization of poly-4-hydroxybutyrate mesh for hernia repair applications.

BACKGROUNDnPhasix mesh is a fully resorbable implant for soft tissue reconstruction made from knitted poly-4-hydroxybutyrate monofilament fibers. The objectives of this study were to characterize the in vitro and in vivo mechanical and resorption properties of Phasix mesh over time, and to assess the functional performance in a porcine model of abdominal hernia repair.nnnMATERIALS AND METHODSnWe evaluated accelerated in vitro degradation of Phasix mesh in 3 mol/L HCl through 120 h incubation. We also evaluated functional performance after repair of a surgically created abdominal hernia defect in a porcine model through 72 wk. Mechanical and molecular weight (MW) properties were fully characterized in both studies over time.nnnRESULTSnPhasix mesh demonstrated a significant reduction in mechanical strength and MW over 120 h in the accelerated degradation in vitro test. In vivo, the Phasix mesh repair demonstrated 80%, 65%, 58%, 37%, and 18% greater strength, compared with native abdominal wall at 8, 16, 32, and 48 wk post-implantation, respectively, and comparable repair strength at 72 wk post-implantation despite a significant reduction in mesh MW over time.nnnCONCLUSIONSnBoth in vitro and in vivo data suggest that Phasix mesh provides a durable scaffold for mechanical reinforcement of soft tissue. Furthermore, a Phasix mesh surgical defect repair in a large animal model demonstrated successful transfer of load bearing from the mesh to the repaired abdominal wall, thereby successfully returning the mechanical properties of repaired host tissue to its native state over an extended time period.

Pediatric palm contact burns: a ten-year review.

Management and proper approach to pediatric palm burns remains unclear. Our burn center’s approach includes early, aggressive range of motion therapy, combined with a period of watchful waiting, reserving grafting only for those palms that do not heal in a timely manner. We reviewed our experience using this approach over a 10-year period. We performed a retrospective review of all pediatric patients with palm burns admitted to our burn center from 1994 to 2004. A total of 168 patients (194 palms) were included in the study. The average patient was 1.3 years old. A total of 168 of the injured palms (87%) healed without need for surgery. The average time to healing was 13 days (range 5–34). The 19 patients (26 palms, 13.4%) who underwent excision and grafting were managed with thick split thickness skin grafts. Of these, four patients (five palms, 19.2%) underwent secondary reconstruction, at an average of 166 days after the initial surgery. Of the 168 (87%) palms managed without surgery, only three patients (four palms) required late reconstruction (2.4%). Reconstructive procedures consisted of full-thickness skin grafts (n = 7) and z-plasty (n = 2). We have found that the majority of patients in this study healed without need for acute or reconstructive surgery. We therefore recommend aggressive hand therapy and conservative surgical management of palm burns in children.

Career plans of graduating plastic surgery trainees in 2009: the impact of an uncertain economic climate.

Background: Trainees in plastic surgery graduating in the midst of the current economic recession face unique financial challenges. These issues have the potential to affect future training and practice plans. Methods: A 13-item questionnaire regarding issues influencing career plans was administered to senior plastic and reconstructive surgery trainees attending the 2009 American Society of Plastic Surgery Senior Residents Conference, in Austin, Texas. Results: Of 97 conference attendees, 57 (58.7 percent) completed the survey representing all regions of the United States (33.3 percent of trainees nationwide). Trainees in the traditional training model (i.e., plastic surgery fellowship after surgery residency) were significantly less likely to pursue additional subspecialty training (29.6 percent) compared with trainees in integrated (76.9 percent) or combined programs (58.8 percent) (p = 0.012). Trainees who have dependents were significantly more likely to go into practice without fellowship (69 versus 38.2 percent, p = 0.031). Outstanding educational debt (>

Remote Liver Injury is Attenuated by Adenovirus-Mediated Gene Transfer of Heme Oxygenase-1 During the Systemic Inflammatory Response Syndrome

50,000 or >

Cotransfection of heme oxygenase-1 prevents the acute inflammation elicited by a second adenovirus

100,000) did not influence future practice plans. Trainees who are concerned about the national economic recession trended toward entering practice without fellowship training (70.0 versus 40.5 percent, p = 0.052). Of the factors surveyed, only anticipated fellowship training was significantly associated with plans to pursue academic practice (p = 0.002). Conclusions: The majority of graduating trainees enter private practice without additional subspecialty fellowship training. Neither exceptional debt nor concern about the current economic recession was the primary determinant of future career plans, whereas trainees in a traditional model of plastic surgery and trainees with dependents were more likely to enter practice without further fellowship training.

Carbon Monoxide Protects Against Hemorrhagic Shock and Resuscitation-Induced Microcirculatory Injury and Tissue Injury

Objectives: Adenovirus‐mediated gene therapy is being investigated with increasing success for future treatment of autoimmune diseases. However, the use of adenoviruses is still limited by inflammatory and immune responses in the target organ. Previous work by the authors laboratory established that the adenovirus encoding inducible heme oxygenase (Ad‐HO‐1) does not elicit the acute hepatic inflammation normally caused by adenoviruses, inviting further investigation in models of severe inflammation. Concurrently, there is increasing evidence for an endogenous protective role for heme oxygenase (HO) in the liver during the systemic inflammatory response syndrome (SIRS). Building on our previous results, this study investigated the effect of Ad‐HO‐1 pretreatment on remote liver injury during normotensive SIRS, induced by bilateral hind limb ischemia and reperfusion.

Low-dose inhaled carbon monoxide attenuates the remote intestinal inflammatory response elicited by hindlimb ischemia-reperfusion

The acute inflammatory response elicited by adenovirus vectors results in loss of gene expression and tissue injury in the target organ. This acute inflammation is now believed to be the major limiting factor for the use of adenovirus vectors in gene therapy. While exploring the level of acute inflammation caused by the adenovirus encoding the gene for the anti-inflammatory enzyme heme oxygenase-1, we discovered that this adenovirus not only did not elicit acute inflammation, but could prevent the inflammation caused by a second adenovirus. Here we describe a new approach to gene therapy, which uses the encoding of the potent anti-inflammatory enzyme heme oxygenase-1 to prevent early host inflammatory responses normally associated with adenovirus vectors.