Toll-like receptor 4 mutation mitigates gut microbiota-mediated hypertensive kidney injury.

Hypertension-associated dysbiosis is linked to several clinical complications, including inflammation and possible kidney dysfunction. Inflammation and TLR4 activation during hypertension result from gut dysbiosis-related impairment of intestinal integrity. However, the contribution of TLR4 in kidney dysfunction during hypertension-induced gut dysbiosis is unclear. We designed this study to address this knowledge gap by utilizing TLR4 normal (TLR4N) and TLR4 mutant (TLR4M) mice. These mice were infused with high doses of Angiotensin-II for four weeks to induce hypertension. Results suggest that Ang-II significantly increased renal arterial resistive index (RI), decreased renal vascularity, and renal function (GFR) in TLR4N mice compared to TLR4M. 16 S rRNA sequencing analysis of gut microbiome revealed that Ang-II-induced hypertension resulted in alteration of Firmicutes: Bacteroidetes ratio in the gut of both TLR4N and TLR4M mice; however, it was not comparably rather differentially. Additionally, Ang-II-hypertension decreased the expression of tight junction proteins and increased gut permeability, which were more prominent in TLR4N mice than in TLR4M mice. Concomitant with gut hyperpermeability, an increased bacterial component translocation to the kidney was observed in TLR4N mice treated with Ang-II compared to TLR4N plus saline. Interestingly, microbiota translocation was mitigated in Ang-II-hypertensive TLR4M mice. Furthermore, Ang-II altered the expression of inflammatory (IL-1ß, IL-6) and anti-inflammatory IL-10) markers, and extracellular matrix proteins, including MMP-2, -9, -14, and TIMP-2 in the kidney of TLR4N mice, which were blunted in TLR4M mice. Our data demonstrate that ablation of TLR4 attenuates hypertension-induced gut dysbiosis resulting in preventing gut hyperpermeability, bacterial translocation, mitigation of renal inflammation and alleviation of kidney dysfunction.

Altered microRNA regulation of short chain fatty acid receptors in the hypertensive kidney is normalized with hydrogen sulfide supplementation.

Hypertension affects nearly one third of the adult US population and is a significant risk factor for chronic kidney disease (CKD). An expanding body of recent studies indicates that gut microbiome has crucial roles in regulating physiological processes through, among other mechanisms, one mode of short chain fatty acids (SCFA) and their target receptors. In addition, these SCFA receptors are potential targets of regulation by host miRNAs, however, the mechanisms through which this occurs is not clearly defined. Hydrogen sulfide (H2S) is an important gasotransmitter involved in multiple physiological processes and is known to alleviate adverse effects of hypertension such as reducing inflammation in the kidney. To determine the role of host microRNAs in regulating short chain fatty acid receptors in the kidney as well as the gut, C57BL/6J wild-type mice were treated with or without Ang-II and H2S donor GYY4137 (GYY) for 4 weeks to assess whether GYY would normalize adverse effects observed in hypertensive mice and whether this was in part due to altered gut microbiome composition. We observed several changes of SCFA receptors, including Olfr78, Gpr41/43 and predicted microRNA regulators in the kidney among the different treatments. Increased expression of inflammatory markers Il6 and Rorc2, along with Tgfß, were found in the hypertensive kidney. The glomerular filtration rate (GFR) was improved in mice treated with Ang-II + GYY compared with Ang-II only, indicating improved kidney function. The Erysipelotrichia class of bacteria, linked with high fat diets, was enriched in hypertensive animals but reduced with GYY supplementation. These data point towards a role for miRNA regulation of SCFA receptors in hypertensive kidney and are normalized by H2S supplementation.

Hydrogen sulfide alleviates hypertensive kidney dysfunction through an epigenetic mechanism.

Hypertension is a major risk factor for chronic kidney disease (CKD), and renal inflammation is an integral part in this pathology. Hydrogen sulfide (H2S) has been shown to mitigate renal damage through reduction in blood pressure and ROS; however, the exact mechanisms are not clear. While several studies have underlined the role of epigenetics in renal inflammation and dysfunction, the mechanisms through which epigenetic regulators play a role in hypertension are not well defined. In this study, we sought to identify whether microRNAs are dysregulated in response to angiotensin II (ANG II)-induced hypertension in the kidney and whether a H2S donor, GYY4137, could reverse the microRNA alteration and kidney function. Wild-type (C57BL/6J) mice were treated without or with ANG II and GYY4137 for 4 wk. Blood pressure, renal blood flow, and resistive index (RI) were measured. MicroRNA microarrays were conducted and subsequent target prediction revealed genes associated with a proinflammatory response. ANG II treatment significantly increased blood pressure, decreased blood flow in the renal cortex, increased RI, and reduced renal function. These effects were ameliorated in mice treated with GYY4137. Microarray analysis revealed downregulation of miR-129 in ANG II-treated mice and upregulation after GYY4137 treatment. Quantitation of proteins involved in the inflammatory response and DNA methylation revealed upregulation of IL-17A and DNA methyltransferase 3a, whereas H2S production enzymes and anti-inflammatory IL-10 were reduced. Taken together, our data suggest that downregulation of miR-129 plays a significant role in ANG II-induced renal inflammation and functional outcomes and that GYY4137 improves renal function by reversing miR-129 expression.NEW & NOTEWORTHY We investigated epigenetic changes that occur in the hypertensive kidney and how H2S supplementation reverses adverse effects. Inflammation, aberrant methylation, and dysfunction were observed in the hypertensive kidney, and these effects were alleviated with H2S supplementation. We identify miR-129 as a potential regulator of blood pressure and H2S regulation.

Hyperhomocysteinemia Alters Sinoatrial and Atrioventricular Nodal Function: Role of Magnesium in Attenuating These Effects.

Patients with hyperhomocysteinemia (HHcy), or elevated plasma homocysteine (Hcy), are at higher risk of developing arrhythmias and sudden cardiac death; however, the mechanisms are unknown. In this study, the effects of HHcy on sinus node function, atrioventricular conduction, and ventricular vulnerability were investigated by electrophysiological (EP) analysis, and the role of magnesium (Mg(2+)), an endogenous N-methyl-D-aspartate (NMDA) receptor antagonist, in attenuating EP changes due to HHcy was explored. Wild-type mice (WT) and mice receiving Hcy in the drinking water for 12 weeks (DW) were subjected to electrocardiographic and EP studies. DW compared to WT had significantly shorter RR, PR, QT, and HV intervals, corrected sinus node recovery times (CSNRT), Wenckebach periodicity (WP), atrioventricular nodal effective refractory periods (AVNERP), and right ventricular effective refractory periods (RVERP). To examine the role of Mg(2+) in mitigating conduction changes in HHcy, WT, DW, and heterozygous cystathionine-ß-synthase knockout mice (CBS (+/-) ) were subjected to repeat EP studies before and after administration of low-dose magnesium sulfate (20 mg/kg). Mg(2+) had no effect on EP variables in WT, but significantly slowed CSNRT, WP, and AVNERP in DW, as well as WP and AVNERP in CBS (+/-) . These findings suggest that ionic channels modulated by Mg(2+) may contribute to HHcy-induced conduction abnormalities.

Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats.

Hypertensive cerebropathy is a pathological condition associated with cerebral edema and disruption of the blood-brain barrier. However, the molecular pathways leading to this condition remains obscure. We hypothesize that MMP-9 inhibition can help reducing blood pressure and endothelial disruption associated with hypertensive cerebropathy. Dahl salt-sensitive (Dahl/SS) and Lewis rats were fed with high-salt diet for 6 weeks and then treated without and with GM6001 (MMP inhibitor). Treatment of GM6001 (1.2 mg/kg body weight) was administered through intraperitoneal injections on alternate days for 4 weeks. GM6001 non-administered groups were given vehicle (0.9% NaCl in water) treatment as control. Blood pressure was measured by tail-cuff method. The brain tissues were analyzed for oxidative/nitrosative stress, vascular MMP-9 expression, and tight junction proteins (TJPs). GM6001 treatment significantly reduced mean blood pressure in Dahl/SS rats which was significantly higher in vehicle-treated Dahl/SS rats. MMP-9 expression and activity was also considerably reduced in GM6001-treated Dahl/SS rats, which was otherwise notably increased in vehicle-treated Dahl/SS rats. Similarly MMP-9 expression in cerebral vessels of GM6001-treated Dahl/SS rats was also alleviated, as devised by immunohistochemistry analysis. Oxidative/nitrosative stress was significantly higher in vehicle-treated Dahl/SS rats as determined by biochemical estimations of malondialdehyde, nitrite, reactive oxygen species, and glutathione levels. RT-PCR and immunohistochemistry analysis further confirmed considerable alterations of TJPs in hypertensive rats. Interestingly, GM6001 treatment significantly ameliorated oxidative/nitrosative stress and TJPs, which suggest restoration of vascular integrity in Dahl/SS rats. These findings determined that pharmacological inhibition of MMP-9 in hypertensive Dahl-SS rats attenuate high blood pressure and hypertension-associated cerebrovascular pathology.

Homocysteine in renovascular complications: hydrogen sulfide is a modulator and plausible anaerobic ATP generator.

Homocysteine (Hcy) is a non-protein amino acid derived from dietary methionine. High levels of Hcy, known as hyperhomocysteinemia (HHcy) is known to cause vascular complications. In the mammalian tissue, Hcy is metabolized by transsulfuration enzymes to produce hydrogen sulfide (H2S). H2S, a pungent smelling gas was previously known for its toxic effects in the central nervous system, recent studies however has revealed protective effects in a variety of diseases including hypertension, diabetes, inflammation, atherosclerosis, and renal disease progression and failure. Interestingly, under stress conditions including hypoxia, H2S can reduce metabolic demand and also act as a substrate for ATP production. This review highlights some of the recent advances in H2S research as a potential therapeutic agent targeting renovascular diseases associated with HHcy.

Matrix Metalloproteinase Inhibition Mitigates Renovascular Remodeling in Salt-Sensitive Hypertension.

Extracellular matrix (ECM) remodeling is the hallmark of hypertensive nephropathy. Uncontrolled proteolytic activity due to an imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases (MMPs/TIMPs) has been implicated in renovascular fibrosis. We hypothesized that inhibition of MMPs will reduce excess ECM deposition and modulate autophagy to attenuate hypertension. Dahl-salt sensitive (Dahl/SS) and Lewis rats were fed on high salt diet and treated without or with 1.2 mg/kg b.w. of GM6001 (MMP inhibitor) by intra-peritoneal injection on alternate days for 4 weeks. Blood pressure, renal cortical blood flow, vascular density, collagen, elastin and MMPs/TIMPs were measured. GM6001 treatment significantly reduced mean blood pressure in hypertensive Dahl/SS rats. Renal resistive index was increased in hypertensive Dahl/SS rats and Doppler flowmetry showed reduced cortical perfusion. Barium angiography demonstrated a reduction in terminal branches of renal vasculature. Inhibition of MMPs by GM6001 resulted in a significant improvement in all the parameters including renal function. In hypertensive Dahl/SS rats, protein levels of MMP-9, -2 and -13 were increased including the activity of MMP-9 and -2; TIMP-1 and -2 levels were increased whereas, TIMP-3 levels were similar to Lewis controls. Administration of GM6001 reduced the activity of MMPs and increased the levels of TIMP-1, -2 and -3. MMP inhibition reduced type -1 collagen deposition and increased elastin in the intra-renal vessels indicating reduced fibrosis. Autophagy markers were decreased in hypertensive Dahl/SS rats and GM6001 treatment enhanced their levels. We conclude that MMP inhibition (GM6001) reduces adverse renovascular remodeling in hypertension by modulating ECM turnover and stimulating autophagy.

Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9.

Matrix metalloproteinase-9 (MMP-9) causes adverse remodeling, whereas hydrogen sulfide (H2S) rescues organs in vascular diseases. The involvement of MMP-9 and H2S in diabetic renovascular remodeling is, however, not well characterized. We determined whether MMP-9 regulates H2S generation and whether H2S modulates connexin through N-methyl-d-aspartate receptor (NMDA-R)-mediated pathway in the diabetic kidney. Wild-type (WT, C57BL/6J), diabetic (Akita, C57BL/6J-Ins2(Akita)), MMP-9(-/-) (M9KO), double knockout (DKO) of Akita/MMP-9(-/-) mice and in vitro cell culture were used in our study. Hyperglycemic Akita mice exhibited increased level of MMP-9 and decreased production of H2S. H2S-synthesizing enzymes cystathionine-ß-synthase and cystathionine-γ-lyase were also diminished. In addition, increased expressions of NMDA-R1 and connexin-40 and -43 were observed in diabetic kidney. As expected, MMP-9 mRNA was not detected in M9KO kidneys. However, very thin protein expression and activity were detected. No other changes were noticed in M9KO kidney. In DKO mice, all the above molecules showed a trend toward baseline despite hyperglycemia. In vitro, glomerular endothelial cells treated with high glucose showed induction of MMP-9, attenuated H2S production, NMDA-R1 induction, and dysregulated conexin-40 and -43 expressions. Silencing MMP-9 by siRNA or inhibition of NMDA-R1 by MK801 or H2S treatment preserved connexin-40 and -43. We conclude that in diabetic renovascular remodeling MMP-9 plays a major role and that H2S has therapeutic potential to prevent adverse diabetic renal remodeling.

Administration of exogenous adenosine triphosphate to ischemic skeletal muscle induces an energy-sparing effect: role of adenosine receptors.

BACKGROUND: Ischemia-reperfusion injury is a devastating complication that occurs in allotransplantation and replantation of limbs. Over the years, several preservation strategies have been used to conserve the critical levels of intracellular adenosine triphosphate (ATP) during ischemia to sustain the ion gradients across the membranes and thus the tissue viability. The administration of exogenous ATP to ischemic tissues is known to provide beneficial effects during reperfusion, but it is unclear whether it provides protection during ischemia. The purpose of the present study was to determine the effect of ATP administration on high-energy phosphate levels in ischemic skeletal muscle and to examine the role of purinergic and adenosine receptors in mediating the response to exogenous ATP. METHODS: The extensor digitorum longus muscles of Fischer rats were subjected to ischemia and treated with different concentrations of ATP with or without purinergic and adenosine receptor blockers. Phosphorus-31 nuclear magnetic resonance spectroscopy was used to measure the rate of decay of ATP, phosphocreatine (PCr), and the formation of adenosine monophosphate and acidification. Phosphorylated compounds were analyzed using a simple model of energy metabolism, and the PCr half-life was used as an index of internal depletion of ATP to distinguish between intracellular and extracellular ATP. RESULTS: PCr decay was rapid in all muscle groups and was followed by gradual ATP decay. The half-life of PCr was significantly longer in the ATP-treated muscles than in the vehicle controls and was maximally prolonged by treating with slow hydrolyzing adenosine 5'-O-(3-thio)triphosphate. Purinoceptor (P2X) blockade with ATP treatment significantly increased the half-life of PCr, and adenosine receptor blockers blunted the response. Administration of adenosine to ischemic muscles significantly increased the half-life of PCr compared with that in the vehicle controls. CONCLUSIONS: Exogenous ATP administration to ischemic skeletal muscles appears to spare intracellular energy by acting primarily through adenosine receptors.

Folic acid mitigates angiotensin-II-induced blood pressure and renal remodeling.

Clinical data suggests an association between systolic hypertension, renal function and hyperhomocysteinemia (HHcy). HHcy is a state of elevated plasma homocysteine (Hcy) levels and is known to cause vascular complications. In this study, we tested the hypothesis whether Ang II-induced hypertension increases plasma Hcy levels and contributes to renovascular remodeling. We also tested whether folic acid (FA) treatment reduces plasma Hcy levels by enhancing Hcy remethylation and thus mitigating renal remodeling. Hypertension was induced in WT mice by infusing Ang II using Alzet mini osmotic pumps. Blood pressure, Hcy level, renal vascular density, oxidative stress, inflammation and fibrosis markers, and angiogenic- and anti-angiogenic factors were measured. Ang II hypertension increased plasma Hcy levels and reduced renal cortical blood flow and microvascular density. Elevated Hcy in Ang II hypertension was associated with decreased 4, 5-Diaminofluorescein (DAF-2DA) staining suggesting impaired endothelial function. Increased expression of Nox-2, -4 and dihydroethidium stain revealed oxidative stress. Excess collagen IV deposition in the peri-glomerular area and increased MMP-2, and -9 expression and activity indicated renal remodeling. The mRNA and protein expression of asymmetric dimethylarginine (ADMA) was increased and eNOS protein was decreased suggesting the involvement of this pathway in Hcy mediated hypertension. Decreased expressions of VEGF and increased anti-angiogenic factors, angiostatin and endostatin indicated impaired vasculogenesis. FA treatment partially reduced hypertension by mitigating HHcy in Ang II-treated animals and alleviated pro-inflammatory, pro-fibrotic and anti-angiogenic factors. These results suggest that renovascular remodeling in Ang II-induced hypertension is, in part, due to HHcy.

Enhancing complement control on endothelial barrier reduces renal post-ischemia dysfunction.

BACKGROUND: Excessive complement activation is an integral part of ischemia and reperfusion (IR) injury (IRI) of organs. In kidney transplantation, the pathologic consequence of IRI and complement activation can lead to delayed graft function, which in turn is associated with acute rejection. Previous strategies to reduce complement-induced IRI required systemic administration of agents, which can lead to increased susceptibility to infections/immune diseases. The objective of this study was to determine whether an increase in complement control defenses of rat kidney endothelium reduces IRI. We hypothesized that increased complement control on the endothelial barrier reduces IR-mediated complement activation and reduces kidney dysfunction. MATERIALS AND METHODS: Fischer 344 rats underwent left kidney ischemia for 45 min and treatment with a novel fusogenic lipid vesicle (FLVs) delivery system to decorate endothelial cells with vaccinia virus complement control protein (VCP), followed by reperfusion for 24 h. Assessment included renal function by serum creatinine and urea, myeloperoxidase assay for neutrophil infiltration, histopathology, and quantification of C3 production in kidneys. RESULTS: Animals in which the kidney endothelium was bolstered by FLVs+VCP treatment had better renal function with a significant reduction in serum creatinine compared with vehicle controls (P < 0.05). Also, C3 production was significantly reduced (P < 0.05) in treated animals compared with vehicle controls. CONCLUSION: Increasing complement control at the endothelial barrier with FLVs+VCP modulates complement activation/production during the first 24 h, reducing renal dysfunction following IRI.

Homocysteine mediated decrease in bone blood flow and remodeling: role of folic acid.

Deficiencies in folate lead to increased serum concentrations of homocysteine (Hcy), which is known as hyperhomocysteinemia (HHcy), is associated with bone disorders. Although, Hcy accumulates collagen in bone and contribute to decrease in bone strength. The mechanism of Hcy induced bone loss and remodeling is unclear. Therefore, the present study was aimed to determine the role of folic acid (FA) in genetically HHcy-associated decrease in bone blood flow and remodeling. Wild type (WT) and cystathionine-ß-synthase heterozygous (CBS+/-) mice were used in this study and supplemented with or without FA (300 mg/kg, Hcy reducing agent) in drinking water for 6 weeks. The tibial bone blood flow was measured by laser Doppler and ultrasonic flow probe method. The tibial bone density (BD) was assessed by dual energy X-ray absorptiometry. The bone homogenates were analyzed for oxidative stress, NOX-4 as oxidative marker and thioredoxin-1 (Trx-1) as anti-oxidant marker, bone remodeling (MMP-9) and bio-availability of nitric oxide (eNOS/iNOS/NO) by Western blot method. The results suggested that there was decrease in tibial blood flow in CBS+/- mice. The BD was also reduced in CBS+/- mice. There was an increase in NOX-4, iNOS, MMP-9 protein as well as MMP-9 activity in CBS+/- mice and decrease in Trx-1, eNOS protein levels, in part by decreasing NO bio-availability in CBS+/- mice. Interestingly, these effects were ameliorated by FA and suggested that FA supplementation may have therapeutic potential against genetically HHcy induced bone loss.

A novel liposome-based therapy to reduce complement-mediated injury in revascularized tissues.

BACKGROUND: Ischemia/reperfusion (IR) injury is an unavoidable consequence of tissue transplantation or replantation that often leads to inflammation and cell death. Excessive complement activation following IR induces endothelial cell injury, altering vascular and endothelial barrier function causing tissue dysfunction. To mitigate the IR response, various systemic anti-complement therapies have been tried. Recently, we developed a localized therapy that uses biotinylated fusogenic lipid vesicles (BioFLVs) to first incorporate biotin tethers onto cell membranes, which are then used to bind therapeutic fusion proteins containing streptavidin (SA) resulting in the decoration of cell membranes. The therapy is applied in two steps using solutions delivered intra-arterially. MATERIALS AND METHODS: Alteration of formulation, concentration and duration of incubation of BioFLVs were conducted to demonstrate the ability of the system to modulate biotin tether incorporation in cultured cells. Using a rat hind limb model, the ability of BioFLVs to decorate endothelium of femoral vessels with FITC-labeled SA for 48 h of reperfusion was demonstrated. The feasibility of a BioFLV-based anti-complement therapy was tested in cultured cells using SA fused with vaccinia virus complement control protein (SA-VCP), a C3 convertase inhibitor. Human ovarian carcinoma (SKOV-3) cells were incubated with BioFLVs first and then with SA-VCP. To activate complement the cells were treated with a SKOV-3-specific antibody (trastuzumab) and incubated in human serum. RESULTS: Decoration of cells with SA-VCP effectively reduced complement deposition. CONCLUSIONS: We conclude that BioFLV-mediated decoration of cell membranes with anti-complement proteins reduces complement activation and deposition in vitro and has the potential for application against inappropropriate complement activation in vivo.

Cell membrane modification for rapid display of bi-functional peptides: a novel approach to reduce complement activation.

Ischemia and reperfusion of organs is an unavoidable consequence of transplantation. Inflammatory events associated with reperfusion injury are in part attributed to excessive complement activation. Systemic administration of complement inhibitors reduces reperfusion injury but leaves patients vulnerable to infection. Here, we report a novel therapeutic strategy that decorates cells with an anti-complement peptide. An analog of the C3 convertase inhibitor Compstatin (C) was synthesized with a hexahistidine (His(6)) tag to create C-His(6). To decorate cell membranes with C-His(6), fusogenic lipid vesicles (FLVs) were used to incorporate lipids with nickel (Ni(2+)) tethers into cell membranes, and these could then couple with C-His(6). Ni(2+) tether levels to display C-His(6) were modulated by changing FLV formulation, FLV incubation time and FLV levels. SKOV-3 cells decorated with C-His(6) effectively reduced complement deposition in a classical complement activation assay. We conclude that our therapeutic approach appears promising for local ex vivo treatment of transplanted organs to reduce complement-mediated reperfusion injury.

Psychosocial considerations in facial transplantation.

The human face and facial transplantation have long captured the interest and imagination of scientists, the media and the lay public. The face is central to our identity, and our communication with the outside world. It is this great importance we attach to our face that makes facial disfigurement such a devastating condition. Facial transplantation could provide an excellent alternative to current treatments for facial disfigurement caused by burns, trauma, cancer extirpation or congenital birth defects. Herein we discuss some of the principal psychosocial considerations which have preceded the clinical introduction of facial transplantation, and which continue today after cases have been performed world-wide.

Clinical considerations in face transplantation.

Severe facial burns cause significant deformities that are technically challenging to treat. Conventional treatments almost always result in poor aesthetic and functional outcomes. This is due to the fact that current treatments cover or replace the delicate anatomical facial tissues with autologus grafts and flaps from remote sites. The recent introduction of clinical composite tissue allotransplantation (CTA) that uses healthy facial tissue transplanted from donors to reconstruct the damaged or non-existing facial tissues with original tissues makes it possible to achieve the best possible functional and aesthetic outcomes in these challenging injuries. The techniques required to perform this procedure, while technically challenging, have been developed over many years and are used routinely in reconstructive surgery. The immunosuppressive regimens necessary to prevent transplanted facial tissue from rejecting (tacrolimus/mycophenolate mofetil/steroid) were developed for and have been used successfully in solid organ transplants for many years. The psychosocial and ethical issues associated with this new treatment have some nuances but generally have many similarities with solid organ and more recently hand transplantation, both of which have been performed clinically for 40 and 10+ years respectively. Herein, we will discuss the technical and immunological aspects of facial tissue transplantation. The psychosocial and ethical issues will be discussed separately in another article in this issue.

Abdominal Wall Reconstruction in a Trauma Setting.

According to the World Health Organization "Global burden of disease study", future demographics of trauma are expected to show an increase in morbidity and mortality. In the past few decades, the field of trauma surgery has evolved to provide global and comprehensive care of the injured. While the modern day trauma surgeon is well trained to deal with multitrauma patients with injuries involving several systems, the ever-increasing nature and variety of multitrauma has left lacuna in certain areas. One such area is the management of abdominal wall injuries, which has been the domain of both plastic and reconstructive and general surgeons. The trauma surgeon is adept at treating the contents of the abdomen but not always the container. If not managed properly complications associated with abdominal wall injuries can lead to increased morbidity and mortality. In considering reconstruction of the abdominal wall in multitrauma patients proper evaluation, scrupulous planning, appropriate, and meticulous technique improve the chances for success with minimal complications. In the present article, we provide a brief description of the most commonly used procedures, and more importantly we outline the principles and guidelines applied to abdominal wall reconstruction in order to inform the trauma surgeon of different available treatment options. In doing so, we hope that this review will assist trauma surgeons in their overall care of patients that present with abdominal injuries.