Molecular Mechanisms Of Injury Research Articles

Topical Alginate Protection against Pepsin-Mediated Esophageal Damage: E-Cadherin Proteolysis and Matrix Metalloproteinase Induction.

Epithelial barrier dysfunction is a hallmark of gastroesophageal reflux disease (GERD) related to symptom origination, inflammatory remodeling and carcinogenesis. Alginate-based antireflux medications were previously shown to topically protect against peptic barrier disruption, yet the molecular mechanisms of injury and protection were unclear. Herein, Barrett's esophageal (BAR-T) cells were pretreated with buffered saline (HBSS; control), dilute alginate medications (Gaviscon Advance or Gaviscon Double Action, Reckitt Benckiser), a viscosity-matched placebo, or ADAM10 and matrix metalloproteinase (MMP) inhibitors before exposure to HBSS pH7.4 or pH4 ± 1 mg/mL pepsin for 10-60 min. Cell viability was assessed by ATP assay; mediators of epithelial integrity, E-cadherin, ADAM10, and MMPs were examined by Western blot and qPCR. Alginate rescued peptic reduction of cell viability (p < 0.0001). Pepsin-pH4 yielded E-cadherin fragments indicative of regulated intramembrane proteolysis (RIP) which was not rescued by inhibitors of known E-cadherin sheddases. Transcriptional targets of E-cadherin RIP fragments were elevated at 24 h (MMP-1,2,9,14; p < 0.01). Alginate rescued E-cadherin cleavage, ADAM10 maturation, and MMP induction (p < 0.01). Results support RIP as a novel mechanism of peptic injury during GERD. Alginate residue after wash-out to mimic physiologic esophageal clearance conferred lasting protection against pepsin-induced molecular mechanisms that may exacerbate GERD severity and promote carcinogenesis in the context of weakly acidic reflux.

Multi-layer perceptron classification & quantification of neuronal survival in hypoxic-ischemic brain image slices using a novel gradient direction, grey level co-occurrence matrix image training.

Hypoxic ischemic encephalopathy (HIE) is a major global cause of neonatal death and lifelong disability. Large animal translational studies of hypoxic ischemic brain injury, such as those conducted in fetal sheep, have and continue to play a key role in furthering our understanding of the cellular and molecular mechanisms of injury and developing new treatment strategies for clinical translation. At present, the quantification of neurons in histological images consists of slow, manually intensive morphological assessment, requiring many repeats by an expert, which can prove to be time-consuming and prone to human error. Hence, there is an urgent need to automate the neuron classification and quantification process. In this article, we present a 'Gradient Direction, Grey level Co-occurrence Matrix' (GD-GLCM) image training method which outperforms and simplifies the standard training methodology using texture analysis to cell-classification. This is achieved by determining the Grey level Co-occurrence Matrix of the gradient direction of a cell image followed by direct passing to a classifier in the form of a Multilayer Perceptron (MLP). Hence, avoiding all texture feature computation steps. The proposed MLP is trained on both healthy and dying neurons that are manually identified by an expert and validated on unseen hypoxic-ischemic brain slice images from the fetal sheep in utero model. We compared the performance of our classifier using the gradient magnitude dataset as well as the gradient direction dataset. We also compare the performance of a perceptron, a 1-layer MLP, and a 2-layer MLP to each other. We demonstrate here a way of accurately identifying both healthy and dying cortical neurons obtained from brain slice images of the fetal sheep model under global hypoxia to high precision by identifying the most minimised MLP architecture, minimised input space (GLCM size) and minimised training data (GLCM representations) to achieve the highest performance over the standard methodology.

Transient Middle Cerebral Artery Occlusion with an Intraluminal Suture Enables Reproducible Induction of Ischemic Stroke in Mice.

Ischemic stroke is a leading cause of mortality and chronic disability worldwide, underscoring the need for reliable and accurate animal models to study this disease's pathology, molecular mechanisms of injury, and treatment approaches. As most clinical strokes occur in regions supplied by the middle cerebral artery (MCA), several experimental models have been developed to simulate an MCA occlusion (MCAO), including transcranial MCAO, micro- or macro-sphere embolism, thromboembolisation, photothrombosis, Endothelin-1 injection, and - the most common method for ischemic stroke induction in murine models - intraluminal MCAO. In the intraluminal MCAO model, the external carotid artery (ECA) is permanently ligated, after which a partially-coated monofilament is inserted and advanced proximally to the common carotid artery (CCA) bifurcation, before being introduced into the internal carotid artery (ICA). The coated tip of the monofilament is then advanced to the origin of the MCA and secured for the duration of occlusion. With respect to other MCAO models, this model offers enhanced reproducibility regarding infarct volume and cognitive/functional deficits, and does not require a craniotomy. Here, we provide a detailed protocol for the surgical induction of unilateral transient ischemic stroke in mice, using the intraluminal MCAO model. Graphic abstract: Overview of the intraluminal monofilament method for transient middle cerebral artery occlusion (MCAO) in mouse.

A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model.

Cerebral ischemic stroke is a leading cause of death and disability, but current pharmacological therapies are limited in their utility and effectiveness. In vitro and in vivo models of ischemic stroke have been developed which allow us to further elucidate the pathophysiological mechanisms of injury and investigate potential drug targets. In vitro models permit mechanistic investigation of the biochemical and molecular mechanisms of injury but are reductionist and do not mimic the complexity of clinical stroke. In vivo models of ischemic stroke directly replicate the reduction in blood flow and the resulting impact on nervous tissue. The most frequently used in vivo model of ischemic stroke is the intraluminal suture middle cerebral artery occlusion (iMCAO) model, which has been fundamental in revealing various aspects of stroke pathology. However, the iMCAO model produces lesion volumes with large standard deviations even though rigid surgical and data collection protocols are followed. There is a need to refine the MCAO model to reduce variability in the standard outcome measure of lesion volume. The typical approach to produce vessel occlusion is to induce an obstruction at the origin of the middle cerebral artery and reperfusion is reliant on the Circle of Willis (CoW). However, in rodents the CoW is anatomically highly variable which could account for variations in lesion volume. Thus, we developed a refined approach whereby reliance on the CoW for reperfusion was removed. This approach improved reperfusion to the ischemic hemisphere, reduced variability in lesion volume by 30%, and reduced group sizes required to determine an effective treatment response by almost 40%. This refinement involves a methodological adaptation of the original surgical approach which we have shared with the scientific community via publication of a visualised methods article and providing hands-on training to other experimental stroke researchers.

A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

Cerebral ischemic stroke is a leading cause of death and disability, but current pharmacological therapies are limited in their utility and effectiveness. In vitro and in vivo models of ischemic stroke have been developed which allow us to further elucidate the pathophysiological mechanisms of injury and investigate potential drug targets. In vitro models permit mechanistic investigation of the biochemical and molecular mechanisms of injury but are reductionist and do not mimic the complexity of clinical stroke. In vivo models of ischemic stroke directly replicate the reduction in blood flow and the resulting impact on nervous tissue. The most frequently used in vivo model of ischemic stroke is the intraluminal suture middle cerebral artery occlusion (iMCAO) model, which has been fundamental in revealing various aspects of stroke pathology. However, the iMCAO model produces lesion volumes with large standard deviations even though rigid surgical and data collection protocols are followed. There is a need to refine the MCAO model to reduce variability in the standard outcome measure of lesion volume. The typical approach to produce vessel occlusion is to induce an obstruction at the origin of the middle cerebral artery and reperfusion is reliant on the Circle of Willis (CoW). However, in rodents the CoW is anatomically highly variable which could account for variations in lesion volume. Thus, we developed a refined approach whereby reliance on the CoW for reperfusion was removed. This approach improved reperfusion to the ischemic hemisphere, reduced variability in lesion volume by 30%, and reduced group sizes required to determine an effective treatment response by almost 40%. This refinement involves a methodological adaptation of the original surgical approach which we have shared with the scientific community via publication of a visualised methods article and providing hands-on training to other experimental stroke researchers.

HUMSC transplantation restores ovarian function in POI rats by inhibiting autophagy of theca-interstitial cells via the AMPK/mTOR signaling pathway

BackgroundPrevious studies of primary ovarian insufficiency (POI) have focused on granulosa cells (GCs) and ignored the role of theca-interstitial cells (TICs). This study aims to explore the mechanism of the protective effects of human umbilical cord-derived mesenchymal stem cells (hUMSCs) on ovarian function in POI rats by regulating autophagy of TICs.MethodsThe POI model was established in rats treated with cisplatin (CDDP). The hUMSCs were transplanted into POI rats by tail vein. Enzyme-linked immunosorbent assay (ELISA) analysis, hematoxylin and eosin (HE) staining, and immunohistochemistry were used to measure the protective effects of hUMSCs. The molecular mechanisms of injury and repairment of TICs were assessed by immunofluorescence, transmission electron microscope (TEM), flow cytometry (FCM), western blot, and quantitative real-time polymerase chain reaction (qRT-PCR).ResultsIn vivo, hUMSC transplantation restored the ovarian function and alleviated the apoptosis of TICs in POI rats. In vitro, hUMSCs reduced the autophagy levels of TICs by reducing oxidative stress and regulating AMPK/mTOR signaling pathway, thereby alleviating the apoptosis of TICs.ConclusionThis study indicates that hUMSCs protected ovarian function in POI by regulating autophagy signaling pathway AMPK/mTOR.

Wound Trauma Exacerbates Acute, but not Delayed, Effects of Radiation in Rats: Mitigation by Lisinopril.

The goal of this study is to understand and mitigate the effects of wounds on acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE), for preparedness against a radiological attack or accident. Combined injuries from concomitant trauma and radiation are likely in these scenarios. Either exacerbation or mitigation of radiation damage by wound trauma has been previously reported in preclinical studies. Female WAG/RijCmcr rats received 13 Gy X-rays, with partial-body shielding of one leg. Within 2 h, irradiated rats and non-irradiated controls were given full-thickness skin wounds with or without lisinopril, started orally 7 days after irradiation. Morbidity, skin wound area, breathing interval and blood urea nitrogen were measured up to 160 days post-irradiation to independently evaluate wound trauma and DEARE. Wounding exacerbated morbidity in irradiated rats between 5 and 14 days post-irradiation (during the ARS phase), and irradiation delayed wound healing. Wounding did not alter delayed morbidities from radiation pneumonitis or nephropathy after 30 days post-irradiation. Lisinopril did not mitigate wound healing, but markedly decreased morbidity during DEARE from 31 through 160 days. The results derived from this unique model of combined injuries suggest different molecular mechanisms of injury and healing of ARS and DEARE after radiation exposure.

Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury

BackgroundCerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia.ResultsFollowing exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition.ConclusionsSex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult—namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke.

Development of mouse models for the study of chloropicrin and hydrogen fluoride ocular injury

The possibility of chemical terrorism within the United States is a rising concern, with the eye being one of the most sensitive tissues to toxicant exposure. We sought to develop mouse models of toxicant-induced ocular injury for the purpose of evaluating potential therapeutics. Chloropicrin (CP) and hydrogen fluoride (HF) were selected for the study owing to their reportedly high potential to induce ocular injury. Eyes of female BALB/c mice were exposed to CP or HF vapor in order to produce a moderate injury, as defined by acute corneal epithelial loss followed by progressive corneal pathology with the absence of injury to deeper eye structures. Clinical injury progression was evaluated up to 12 weeks postexposure, where a significant dose-dependent induction of corneal neovascularization was measured. Histopathology noted epithelial necrosis and stromal edema as early as 24 h after exposure but was resolved by 12 weeks. A significant increase in inflammatory cytokine concentrations was measured in the cornea 24 h after exposure and returned to baseline by day 14. The ocular injury models we developed here for CP and HF exposure should serve as a valuable tool for the future evaluation of novel therapeutics and the molecular mechanisms of injury.

Molecular Mechanisms of Injury in HIV-Associated Nephropathy.

HIV-associated nephropathy (HIVAN) is an important cause of secondary focal glomerulosclerosis that occurs primarily in persons of African ancestry with advanced HIV disease. Although HIVAN is characterized by severe proteinuria and rapid progression to end stage renal disease without treatment, the phenotype is markedly attenuated by treatment with antiretroviral medications. HIV infection of glomerular and tubular epithelial cells and subsequent viral gene expression is a key contributor to HIVAN pathogenesis and the kidney can serve as reservoir for HIV strains that differ those in blood. HIV gene expression in renal epithelial cells leads to dysregulation of cellular pathways including cell cycle, inflammation, cell death, and cytoskeletal homeostasis. Polymorphisms in the APOL1 gene explain the marked predilection of HIVAN to occur in persons of African descent and HIVAN. Since HIVAN has the strongest association with APOL1 genotype of any of the APOL1-associated nephropathies, studies to determine the mechanisms by which HIV and APOL1 risk variants together promote kidney injury hold great promise to improve our understanding of the pathogenesis of APOL1-mediated kidney diseases.

Murine Model of Intestinal Ischemia-reperfusion Injury.

Intestinal ischemia is a life-threatening condition associated with a broad range of clinical conditions including atherosclerosis, thrombosis, hypotension, necrotizing enterocolitis, bowel transplantation, trauma and chronic inflammation. Intestinal ischemia-reperfusion (IR) injury is a consequence of acute mesenteric ischemia, caused by inadequate blood flow through the mesenteric vessels, resulting in intestinal damage. Reperfusion following ischemia can further exacerbate damage of the intestine. The mechanisms of IR injury are complex and poorly understood. Therefore, experimental small animal models are critical for understanding the pathophysiology of IR injury and the development of novel therapies. Here we describe a mouse model of acute intestinal IR injury that provides reproducible injury of the small intestine without mortality. This is achieved by inducing ischemia in the region of the distal ileum by temporally occluding the peripheral and terminal collateral branches of the superior mesenteric artery for 60 min using microvascular clips. Reperfusion for 1 hr, or 2 hr after injury results in reproducible injury of the intestine examined by histological analysis. Proper position of the microvascular clips is critical for the procedure. Therefore the video clip provides a detailed visual step-by-step description of this technique. This model of intestinal IR injury can be utilized to study the cellular and molecular mechanisms of injury and regeneration.

Murine Model of Intestinal Ischemia-reperfusion Injury

Intestinal ischemia is a life-threatening condition associated with a broad range of clinical conditions including atherosclerosis, thrombosis, hypotension, necrotizing enterocolitis, bowel transplantation, trauma and chronic inflammation. Intestinal ischemia-reperfusion (IR) injury is a consequence of acute mesenteric ischemia, caused by inadequate blood flow through the mesenteric vessels, resulting in intestinal damage. Reperfusion following ischemia can further exacerbate damage of the intestine. The mechanisms of IR injury are complex and poorly understood. Therefore, experimental small animal models are critical for understanding the pathophysiology of IR injury and the development of novel therapies. Here we describe a mouse model of acute intestinal IR injury that provides reproducible injury of the small intestine without mortality. This is achieved by inducing ischemia in the region of the distal ileum by temporally occluding the peripheral and terminal collateral branches of the superior mesenteric artery for 60 min using microvascular clips. Reperfusion for 1 hr, or 2 hr after injury results in reproducible injury of the intestine examined by histological analysis. Proper position of the microvascular clips is critical for the procedure. Therefore the video clip provides a detailed visual step-by-step description of this technique. This model of intestinal IR injury can be utilized to study the cellular and molecular mechanisms of injury and regeneration.

Chapter 5 - Cellular and molecular mechanisms of injury and spontaneous recovery

Until recently, most have assumed that traumatic brain injury (TBI) was singularly associated with the overt destruction of brain tissue resulting in subsequent morbidity or death. More recently, experimental and clinical studies have shown that the pathobiology of TBI is more complex, involving a host of cellular and subcellular changes that impact on neuronal function and viability while also affecting vascular reactivity and the activation of multiple biological response pathways. Here we review the brain's response to injury, examining both focal and diffuse changes and their implications for post-traumatic brain dysfunction and recovery. TBI-induced neuronal dysfunction and death as well as the diffuse involvement of multiple fiber projections are discussed together with considerations of how local axonal membrane changes or channelopathy translate into local ionic dysregulation and axonal disconnection. Concomitant changes in the cerebral microcirculation are also discussed and their relationship with the parallel changes in the brain's metabolism is considered. These cellular and subcellular events occurring within neurons and their blood supply are correlated with multiple biological response modifiers evoked by generalized post-traumatic inflammation and the parallel activation of oxidative stress processes. The chapter closes with considerations of recovery following focal or diffuse injury. Evidence for dynamic brain reorganization/repair is presented, with considerations of traumatically induced circuit disruption and their progression to either adaptive or in some cases, maladaptive reorganization.

Differentially expressed genes and pathways induced by organophosphates in human neuroblastoma cells

Organophosphates (OPs) are toxic chemicals commonly used as pesticides and herbicides. Some OPs are highly toxic to humans and have been used in warfare and terrorist attacks. In order to elucidate the molecular mechanisms of injury caused by OPs, the differentially expressed genes were analyzed in human SK-N-SH neuroblastoma cells induced by three OPs. The SK-N-SH cells were treated with one of the three OPs, chlorpyrifos, dichlorvos or methamidophos at LC20 (high-dose), the concentration causing 20% cell death, as well as 1/20 of LC20 (low-dose), a sub-lethal concentration with no detectable cell death, for 24 h. The genome-wide gene changes were identified by Agilent Microarray System, and analyzed by microarray analysis tools. The analysis revealed neuroblastoma cells treated with the high doses of all three OPs markedly activated cell apoptosis and inhibited cell growth and proliferation genes, which would most likely lead to the process of cell death. Interestingly, the analysis also revealed significant decrease in expressions of many genes in a specific spliceosome pathway in cells treated with the low doses of all three different OPs. The change of spliceosome pathway may represent an important mechanism of injury in neuronal cells exposed to low doses of various OPs. In addition to unraveling a potentially different form of OP pathogenesis, this finding could provide a new diagnostic marker in assessing OP-associated injury in cells or tissues. In addition, these results could also contribute to the development of new prevention and/or therapeutic regimens against OP toxicity.

Cold Intravascular Organ Perfusion for Renal Hypothermia During Laparoscopic Partial Nephrectomy

We report initial data on the safety and functional outcomes of renal hypothermia with arterial cold perfusion during partial nephrectomy. From June 2007 to June 2009, 31 consecutive patients underwent laparoscopic partial nephrectomy with hypothermia using renal arterial perfusion with cold, lactated Ringer's solution during renal ischemia. Doppler echography was done intraoperatively to evaluate renal perfusion. Complication data were reported prospectively. Median followup was 57 weeks (IQR 28, 83). The lowest recorded renal temperature during ischemia was 14C. Median tumor size was 4.0 cm (IQR 2.7, 6.2). Median estimated blood loss was 150 cc (IQR 100, 275). Median ischemia time was 35 minutes (IQR 26, 41). Doppler echography identified intrarenal arterial blood flow postoperatively in all cases. The median change in the estimated glomerular filtration rate from preoperatively to postoperative day 2 was 4 ml per minute (IQR -29, 19). Two months postoperative in 20 patients the median change was 3.5 ml per minute (IQR -6, 16.5). At last followup in 31 patients the overall change in the estimated glomerular filtration rate was -0.5 ml per minute (IQR -6, 6). Six complications developed in a total of 5 patients, of which 5 were grade 2 or less. One grade 3 postoperative hemorrhage from an arteriovenous fistula at the tumor resection site was treated with angiography and selective embolization. Cold intravascular perfusion during laparoscopic partial nephrectomy can achieve renal hypothermia below 15C. It is not associated with an immediate risk of renal vascular injury or thrombosis, as measured by Doppler echography in this series. Early changes in postoperative estimates of renal function appear minimal.

Abstract 2837: Delayed Calpain Inhibition Is Neuroprotective After Transient Global Brain Ischemia

Introduction/Hypothesis: The delay in neurodegeneration after transient global brain ischemia offers a potentially broad therapeutic window for inhibiting molecular injury mechanisms. One such mechanism, calpain-mediated proteolysis, peaks between 24 and 72 hours after transient forebrain ischemia (TFI) in rats. This study tests the hypothesis that calpain inhibition is neuroprotective when initiated 22 hours after TFI. Methods: Male Long Evans rats (400 – 450 g) were anesthetized (halothane), mechanically ventilated, and instrumented for temperature and hemodynamic monitoring. Each underwent 10 minutes of TFI induced by reversible bilateral carotid occlusion and hypovolemic hypotension (MAP 30 mm Hg). Twenty-two hours after TFI, rats were block randomized (n=6/group) to receive either calpain inhibitor (CEP-3453 (Cephalon), 60 mg/kg IV bolus and 30 mg/kg IV infusion for 50 hours) or vehicle (normal saline IV bolus and infusion for 50 hours). Sham operated rats served as controls. Rats were euthanized 72 hours after injury and brains were processed for immunohistochemistry. Hippocampal CA1 sector calpain activity was analyzed by immunofluorescence using primary antibody that specifically detects calpain-cleaved alpha-spectrin (Ab38). Neurodegeneration was quantified by counting normal appearing Hoechst-stained neuronal nuclei in the hippocampal CA1 pyramidal layer. Ab38 immunofluorescence intensity and normal nuclei counts were compared between vehicle and CEP-3453 treatment groups using a two-tailed Student’s t-test (alpha error 0.05). Results: Baseline and post-injury hemodynamic parameters and temperature were not significantly different between vehicle and CEP-3453 treatment groups. Relative to sham operated controls, mean CA1 sector Ab38 immunofluorescence increased by 263 ± 281% in vehicle treated rats and 68 ± 147% in CEP-3453 treated rats (p=0.17). Normal CA1 pyramidal layer nuclei averaged 10 ± 12% of control in vehicle treated rats and 50 ± 42% of control in CEP-3453 treated rats (p=0.047). Conclusion: These results suggest a causal role for calpains in delayed post-ischemic neurodegeneration, and demonstrate a broad therapeutic window for calpain inhibition in this model of transient global brain ischemia.

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Since the adult respiratory distress syndrome was first described substantial progress has been made in understanding the pathogenesis of this complex syndrome. This review summarizes our current understanding of the pathophysiology of what is now termed the acute respiratory distress syndrome (ARDS) and its less severe form acute lung injury (ALI), with an emphasis on cellular and molecular mechanisms of injury that may represent potential therapeutic targets. Although it is difficult to synthesize all of these abnormalities into a single, unified, pathogenetic pathway, a theme that emerges repeatedly is that of imbalance, be it between pro- and anti-inflammatory cytokines, oxidants and antioxidants, procoagulants and anticoagulants, neutrophil recruitment and activation and mechanisms of neutrophil clearance, or proteases and protease inhibitors. Future therapies aimed at restoring the overall balance of cytokines, oxidants, coagulants, and proteases may ultimately be successful where therapies that target individual cytokines or other mediators have not.

Air Pollution-Related Illness: Effects of Particles

Particle pollutants are estimated to cause more than 500,000 deaths annually. In his perspective, Nel describes how the adverse effects of ultrafine air particles are linked to their ability to gain access to the lung and systemic circulation, where toxic components lead to tissue damage and inflammation. Increased insight into which particle components are most damaging, and the molecular mechanisms of injury, will help to prevent PM mortality.

Optimum Pharmacologic Management of an Acute Spinal Cord Injury in the Setting of a Lumbar Burst Fracture

Spinal cord injury is a devastating disease that has eluded successful treatment. It has been a long-held belief that most injuries are untreatable. This view is changing as new discoveries are made into the molecular mechanisms of injury and regeneration. This insight has led to the pursuit of new avenues of pharmacotherapy. Although surgical treatment varies with injuries at different levels, pharmacologic management for a lumbar spine burst fracture with spinal cord injury is no different than injuries at other levels. This review will describe some of the inroads made into spinal cord injury and discuss what treatments are now available and what may be in store for the future.

Cell biology and molecular mechanisms of injury in ischemic acute renal failure.

The pathogenesis of acute renal failure has been attributed to persistent vasoconstriction and leukocyte-endothelial interactions, resulting in inflammation and compromise of local blood flow to the outer medulla, the loss of tubular epithelial cell polarity with multiple functional sequelae, necrosis or apoptosis of epithelial cells, and the de-differentiation, migration and proliferation of surviving cells. In this paper, the authors present their views of pathophysiology of ischemic acute renal failure.