Emanuela Ricciotti, PharmD, PhD

• Research Assistant Professor
• Research Expertise: Genomic, proteomic and metabolomics analysis of inflammatory pathways in vascular cells

https://www.med.upenn.edu/fitzgeraldlab/personnel.html

There is genetic variation in the regulation of specific proteins that may or may not be unique to the alveolar macrophage blood pressure chart cdc order digoxin 0.25 mg online. Other issues are unique when comparing alveolar macrophages from animals to humans blood pressure question order 0.25 mg digoxin fast delivery. The majority of animal studies are done with mice and rats with fewer studies in guinea pigs and rabbits heart attack survival rate digoxin 0.25 mg purchase without prescription. Other occasional studies have used such sources as ovine and bovine blood pressure good range order digoxin 0.25 mg line, but in general those studies are not intended for human extrapolation blood pressure quit drinking discount digoxin 0.25 mg buy line. With rare exception, humans have been subjected to various respiratory tract infections and other airborne contaminants. Even within murine strains there are differences in sensitivity of alveolar macrophages to xenobiotics (Li et al. Therefore, there are differences between animal and human alveolar macrophage responses to xenobiotics, and caution needs to be taken to ensure that the animal model accurately reflects the human disease. It is likely that older, very loosely adherent cells are removed first by lung lavage followed by younger (and smaller) more tightly adherent cells upon repeated lung washings (Dauber et al. Ideally, macrophages should be cultured as a sparse (not confluent) layer on epithelial cultures (possibly on porous filters for feeding) with a thin film of surfactant (lung lining fluid) covering, allowing alveolar macrophages to be exposed to a high oxygen environment. Various investigators have models that are in partial agreement, but this is a very difficult system to accurately replicate in vitro. Investigators have to use relatively dense cultures of macrophages in order to have enough material for bioassays. Since the alveolar macrophage releases many factors with autocrine effects (compare Tables 1 and 2), this would impact many functional responses in vitro in an unknown manner. Furthermore, since the alveolar macrophage responds to factors released by many other lung cells, as well as to other unique factors in the lung lining fluid, it is likely that the macrophage phenotype changes after isolation and culture. The dose of a gas or particulate to the alveolar macrophage in vivo is also difficult to model in vitro. Particulates will most likely be opsonized by lung lining fluid components before encountering macrophages. Gas solubility and reactivity in the lung lining fluid layer may affect the concentration reaching the alveolar macrophage. Alternatively, reactive intermediates may be generated in the lung lining fluid layer. Consequently, it may be possible to obtain artifactual negative or positive results in vitro. Potentially the most effective use of in vitro models is to define a specific function and confirm with in vivo or ex vivo data. The key would be to reproduce a particular functional outcome following exposure to the xenobiotic. The most common one uses macrophages adherent on a glass or plastic surface under a relatively thick layer of medium (compared to the thin layer of lung lining fluid) containing 1%­10% serum. The major drawback of this model is that since the alveolar macrophage is not a tightly adherent cell in the lung, it responds to the artificial surface as foreign material that needs to be ingested, and consequently the macrophage can become activated. The alveolar macrophage cell density is much higher and the oxygen tension is lower than physiological. In addition, the fluid layer thickness and composition is different from the in vivo environment. A second procedure uses macrophages in rotating suspension culture in medium containing serum. In this model the macrophages are not activated by adherence, the oxygen tension is uniform and higher than adherent tissue culture, but the same limitations apply regarding the fluid composition. Therefore, it is necessary to consider significant limitations of in vitro cell cultures using macrophages when extrapolating to in vivo. Other aspects of macrophage activity have likewise been observed to be different between primary and transformed cells. For example, the regulation and intracellular processing of cytokines has been reported to be different in U937 cells compared to human alveolar macrophages (Hass et al. However, these cell lines are useful for mechanistic studies once it has been established that a particular cell line is a relevant model for a specific purpose or agent. Due to its important functions and location in the lungs the macrophage is a critical target for xenobiotic-mediated lung injury. Xenobiotic agents have been implicated in various forms of lung injury from inducing immunosuppression to chronic inflammation through effects on the alveolar macrophage. There are still undiscovered cytokines and even responses of the alveolar macrophage, as well as mechanisms of xenobiotic action that will alter our thinking in the future. Plasticity of macrophage phenotypes may be central to regulate the fine balance required for normal lung physiology. Streptococcus pneumoniae-associated human macrophage apoptosis after bacterial internalization via complement and Fcgamma receptors correlates with intracellular bacterial load. Systematic validation of specific phenotypic markers for in vitro polarized human macrophages. Cutting edge: Biasing immune responses by directing antigen to macrophage Fc gamma receptors. Ozone stimulates synthesis of inflammatory cytokines by alveolar macrophages in vitro. Increase of bovine alveolar macrophage superoxide anion and hydrogen peroxide release by dusts of different origin. Cytokine modulation of the immunosuppressive phenotype of pulmonary alveolar macrophage populations. Role of macrophage replication in modulating the increased number of alveolar macrophages in chronic inflammatory lung disorders. Pulmonary intravascular macrophages: Their contribution to the mononuclear phagocyte system in 13 species. Role of granulocyte/macrophage colony-stimulating factor in the regulation of murine alveolar macrophage proliferation and differentiation. Effects of fine and ultrafine sulfuric acid aerosols in guinea pigs: Alterations in alveolar macrophage function and intracellular pH. Lipopolysaccharides may aggravate apoptosis through accumulation of autophagosomes in alveolar macrophages of human silicosis. Heavy metals and metalloids as autophagy inducing agents: Focus on cadmium and arsenic. The response of guinea pig airway epithelial cells and alveolar macrophages to environmental stress. Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in vivo. Phagocytosis and chemotaxis of rat alveolar macrophages after a combined or separate exposure to ozone and carbon black. Separation of bronchoalveolar cells from the guinea pig on continuous density gradients of Percoll: Morphology and cytochemical properties of fractionated lung macrophages. Interaction of alveolar macrophages with Nocardia asteroides: Immunological enhancement of phagocytosis, phagosome-lysosome fusion, and microbicidal activity. Ozone-induced release of cytokines and fibronectin by alveolar macrophages and airway epithelial cells. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Immune-mediated phagocytosis and killing of Streptococcus pneumoniae are associated with direct and bystander macrophage apoptosis. Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection. In vitro fibrinolytic activity and viability of rat alveolar macrophages treated with inflammation generating mineral dusts. Stimulation of rat alveolar macrophage fibronectin release in a cadmium chloride model of lung injury and fibrosis. Asbestos fibers and silica particles stimulate rat alveolar macrophages to release tumor necrosis factor. Endotoxin lipopolysaccharide from Escherichia coli and its effects on the phagocytic function of systemic and pulmonary macrophages in turkeys. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. The relation of pulmonary pathology to clinical course and prognosis based on a study of 130 cases from the U. Scaling morphometric pulmonary diffusing capacity to body mass: Wild and domestic mammals. Stimulatory and inhibitory signals originating from the macrophage Fcgamma receptors. A comparison of the pulmonary defenses against streptococcal infection in rats and mice following O3 exposure: Differences in disease susceptibility and neutrophil recruitment. New insights into the multidimensional concept of macrophage ontogeny, activation and function. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals. Tumor-associated macrophages promote invasion while retaining Fc-dependent anti-tumor function. The effect of size on Ag nanosphere toxicity in macrophage cell models and lung epithelial cell lines is dependent on particle dissolution. Synthesis, characterization, and bioactivity of carboxylic acid-functionalized titanium dioxide nanobelts. Phagocytosis, bacterial killing, and metabolism by purified human lung phagocytes. Separation of bronchoalveolar cells from the guinea pig on continuous gradients of Percoll: Functional properties of fractionated lung macrophages. Down-regulation of immune responses in the lower respiratory tract: the role of alveolar macrophages. Lung lining fluid modification of asbestos bioactivity for the alveolar macrophage. Respiratory aflatoxicosis: Suppression of pulmonary and systemic host defenses in rats and mice. Evaluation of the phenotype pattern of macrophages isolated from malignant and non-malignant pleural effusions. Kinetics of central nervous system microglial and macrophage engraftment: Analysis using a transgenic bone marrow transplantation model. Relative release of interleukin-1 beta and interleukin-1 receptor antagonist by alveolar macrophages. A study in asbestos-induced lung disease, sarcoidosis, and idiopathic pulmonary fibrosis. Isolation and partial characterization of subpopulations of alveolar macrophages, granulocytes, and highly enriched interstitial macrophages from rat lung. Pulmonary and thoracic macrophage subpopulations and clearance of particles from the lung. Interference in autophagosome fusion by rare earth nanoparticles disrupts autophagic flux and regulation of an interleukin-1beta producing inflammasome. Single-cell imaging of caspase-1 dynamics reveals an all-or-none inflammasome signaling response. Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Nitric oxide levels regulate macrophage commitment to apoptosis or necrosis during pneumococcal infection. Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. Decreased alveolar macrophage apoptosis is associated with increased pulmonary inflammation in a murine model of pneumococcal pneumonia. Resident alveolar macrophages are replaced by recruited monocytes in response to endotoxin-induced lung inflammation. Adipose tissue macrophages: Phenotypic plasticity and diversity in lean and obese states. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Granulocyte-alveolar-macrophage interaction in the pulmonary clearance of Staphylococcus aureus. Decline in the phagocytic function of alveolar macrophages from mice exposed to cigarette smoke. Autophagic clearance of bacterial pathogens: Molecular recognition of intracellular microorganisms. Enhanced production of interleukin-1, tumor necrosis factor-alpha, and fibronectin by rat lung phagocytes following inhalation of a pulmonary irritant. In vitro bioactivity of asbestos for the human alveolar macrophage and its modification by IgG. Human alveolar macrophage cytokine release in response to in vitro and in vivo asbestos exposure. Alveolar macrophage kinetics and multinucleated giant cell formation after lung injury. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Spectrum of immunoregulatory functions and properties of human alveolar macrophages. Characterization of the lower respiratory tract inflammation of nonsmoking individuals with interstitial lung disease associated with chronic inhalation of inorganic dusts.

Because many of the perinatal exposures known to program lung disease take place in the second half of human gestation blood pressure quizzes digoxin 0.25 mg mastercard, this discussion will be limited to animal models that focus on the last stage of lung development arrhythmia etiology buy digoxin 0.25 mg low price, i hypertension 32 years old purchase 0.25 mg digoxin with amex. Finally heart attack 38 years old purchase digoxin 0.25 mg otc, Environmental Exposures and Developmental Programming of the Lung 155 the alveolar stage begins at gestational week 32 and continues postnatally (Burri heart attack follow me order digoxin once a day, 2006; Albertine and Pysher, 2004). Alveolar numbers in the human lung increase sharply during the first 2 years of life, and continue to increase through adolescence (Herring et al. When the lung is in the saccular stage, the lung parenchyma is composed of smooth-walled sacks lined by cuboidal epithelial cells. The transformation is characterized by formation and elongation of secondary septa, and subdivision of the saccules into alveoli. The process of transformation of lung saccules into alveoli requires thinning of the saccule walls by apoptosis, as well as capillary growth and expansion into the epithelial cells. Lung development in nonhuman mammalian species follows the same distinct stages as human lung development, albeit with altered timing relative to term birth. The closest in developmental timing to the human lung is the nonhuman primates, with timing of alveolar formation nearly identical to the human lung (Herring et al. In other large animal models such as the sheep, alveolar formation also begins before term birth and continues postnatally (Albertine, 2015). In sheep, again similar to humans, the alveolar epithelium differentiates, and a large increase in pulmonary capillary surface area occurs prenatally (Alcorn et al. The lung of rats and mice however, differs significantly from the human lung in the timing of alveolar formation. At term birth, the rat and mouse lung is in the saccular stage of development, with alveolar formation occurring at approximately postnatal day 4 (Burri et al. Alveolar growth continues exponentially through day 20 in the rat and mouse lung (Herring et al. An important caveat is that newborn rats and mice pups that have lungs in the saccular stage of development do not require ventilatory support to survive. Most importantly, the preterm lamb model recapitulates the human clinical occurrence of preterm birth that is frequently associated with respiratory distress and failure. Newborn piglet models of pulmonary hypertension are also used, and have greatly added to the field (Fike et al. In addition to lung development relative to birth that is comparable to the human lung, an advantage of large animal models for studies is that clinical diagnostic techniques, such as catheterization, are possible. In addition, large-animal models have larger blood volumes, greater vessel access, and a generous tissue supply, making it possible to perform clinically relevant assessments (Aguero et al. Rat and mouse models are commonly used for research into the programming of lung disease. While timing of alveolar formation, relative to birth differs from that of the human lung, this feature can be exploited experimentally. Immaturity of the rat and mouse lung at birth allows postnatal experimental manipulation during the saccular and early alveolar stages of lung development without the complication of preterm birth. A second strength of rat and mouse models is rapid gestational and postnatal development, as well as large litter numbers. These factors facilitate experimental study design, and allow for cost effective use of larger sample sizes. Larger sample sizes allows for greater statistical power to differentiate biological effects, as well as the ability to include all relevant biological variables, such as sex, in the analysis. Finally, a significant strength of rat and mouse models is the ability manipulate genetic material. Rat and mouse models are frequently used to study the effects of perinatal events on lung outcomes. These models include perinatal exposure to maternal toxins and tobacco smoke, placental insufficiency, malnutrition, and postnatal oxygen toxicity (Joss-Moore et al. Exposures can be delivered before birth, or after birth, and with or without an additional second hit. The ability to control extraneous environmental variables allows determination of the mechanisms by which perinatal exposures program lung disease. Animal models of perinatal exposures should ideally be validated for the exposure and the outcome have correlations to the human condition, and be followed long term. Important milestones that should be considered in research aimed at understanding the programming of lung disease include several factors. In the case of maternal toxic exposures, maternal and fetal levels of the toxicant should be evaluated. Many experimental studies utilize exposures greater than that typically encountered in humans, in order to elicit effects. This approach is often necessary, but should be considered during the interpretation of findings. On the other hand, an exposure such as maternal tobacco smoke can be optimized using well-designed smoke exposure systems with protocols designed to mimic maternal and fetal cotinine levels found in human smokers (Zinkhan et al. In the programming of lung disease studies, the development of the lung is an important feature. Lung structural parameters should be evaluated at the time of exposure and through the remainder of development. Alternations in lung mechanics following perinatal exposures can often be correlated to a human condition, and may also highlight subtle changes to the lung that predispose to long-term disease. Long-term changes in lung structure and function should also be assessed, particularly with the addition of second hits, such as hyperoxia and tobacco smoke. Lung structure and function data, accompanied by molecular insights allows for determination of pathways that are perturbed by perinatal exposures. An understanding of the mechanisms of programming of lung disease also provides an opportunity to assess interventions and windows of efficacy. A common and significant theme in animal models of perinatal exposures is the development of alterations in lung structure and function, as well as susceptible pathways and gene targets. A well-studied maternal exposure is that of in utero exposure to maternal tobacco smoke, or isolated nicotine. The effects of maternal tobacco smoke or nicotine have been investigated in rats, mice, sheep, and nonhuman primates. Constant findings include alterations in lung growth and in the formation of alveoli (Rehan et al. Mechanisms by which alveolar formation is effected appear multifactorial, and involve perturbations to many important lung developmental signaling pathways. Effects of isolated nicotine exposure in the perinatal period on lung development are similar to those produced by maternal tobacco smoke exposure. Maternal nicotine administration alters lung growth and causes alveolar impairment in sheep, rats, and nonhuman primates (Sandberg et al. In the lung regions with increased a7 expression, increased collagen around large airways and vessels is also observed (Sekhon et al. Effects of maternal tobacco smoke and isolated nicotine exposure also affect lung growth and development via alterations in immune function. Classical activation or "M1 polarization" of alveolar macrophages is mediated by type 1 helper T-cells (Th1), and results in expression of genes relevant to inflammation and cell-mediated immunity. In contrast, macrophage "M2 polarization," induced by type 2 helper T-cells (Th2) induces expression of receptors with scavenger functions, antiinflammatory cytokines, and molecules implicated in tissue remodeling (Shaykhiev et al. Similarly, prenatal exposure to nicotine induced a Th2 dominant immune environment in the lung, and promotes M2 polarization of macrophages. Animal models have also shed light on the effects of prenatal exposures on the response to postnatal second hit. Mice exposed to second-hand smoke during the prenatal period were reexposed to second-hand smoke in adulthood. Compared to mice with no exposure, or exposure during either the prenatal period or the postnatal period (but not both), mice with prenatal and postnatal exposures had lung remodeling with increased collagen deposition, increased proinflammatory cytokines gene expression, and increased profibrotic gene expression (Xiao et al. Impaired alveolar formation, decreased alveolar number, and decreased internal surface area are evident in sheep and baboons born preterm and managed with mechanical ventilation (Albertine et al. Oxygen toxicity contributes, at least in part, to altered lung structure in preterm animals managed with mechanical ventilation. When the immature lungs of newborn mice are exposed to hyperoxia (65% O2) in the neonatal period, the lung in adulthood is altered and lung function is reduced. The severity and timing of perinatal exposures affects the response of the lung, both in terms of severity and lung phenotype (JossMoore and Lane, 2009; Harding and Maritz, 2012; Briana and Malamitsi-Puchner, 2012). These early changes in alveolar structure result in a lung with different inherent characteristics. Notably, the gene expression changes, and resulting gene characteristics altered by perinatal insults become the basis upon which additional growth and development, as well as response to injury are set. Gene expression and the regulation of gene expression are governed by epigenetics. Regulation of gene expression is maintained by epigenetic Environmental Exposures and Developmental Programming of the Lung 157 mechanisms. Throughout development, and beyond, genes may be turned on or off have expression that is increased or decreased in magnitude, and have expression localized to specific cells. This spatial and temporal regulation of gene expression is controlled by interactions between the transcription machinery, transcriptional coactivators and repressors, and the epigenetic code. Excellent reviews of the general mechanisms of transcription and epigenetic regulation of gene expression are available (Voss and Hager, 2014; Klose and Bird, 2006; Zentner and Henikoff, 2013). Because of this, each cell type has a unique epigenetic profile, or pattern of epigenetic marks. When perinatal insults alter that unique pattern, altered gene expression, and alterations in the cellular characteristics result. Spatial and temporal changes in the expression of genes that govern lung growth and development, as well as reprogramming of lung cells, alter the immediate response of the lung, and primes the lung for altered responses to future insults. While genetic susceptibility is also an important component of developmental programming here we will focus only on epigenetics because epigenetic regulation is responsive to environmental cues, such as toxin exposure. Within the developing lung, there are three major consequences of altered epigenetics and gene expression. First, lung structure and/or function may be altered secondary to changes in cell differentiation and cell-to-cell communications. The second effect of altered epigenetic profiles involves the concept that throughout development the epigenetic profile of the genome is dynamic and changes to produce a developmentally appropriate expression profile. When the epigenome of a cell is altered at a developmentally sensitive time point, the "new" epigenetic platform becomes the basis upon which subsequent epigenetic changes are built. The effect of altering the epigenome during development is an increasing deviation from "normal" during and after development. The third consequence of changing lung cell epigenetics during development is an epigenome that is primed to direct gene expression differently in response to a second hit. However, whether epigenetic phenomena are causative in the programming of lung disease, or a biomarker of an event, this is an important arena of study. CpG motifs may be clustered in dense regions known as CpG "islands," or dispersed at low density throughout the genome (Gardiner-Garden and Frommer, 1987). CpG islands are commonly found in promoter regions of mammalian genes, and are often unmethylated in transcriptionally active genes (Huh et al. Unlike promoter regions, coding regions and regions between genes contain a low density of CpGs. These intergenic and intragenic CpGs and are more frequently methylated, and may be associated with regulation of alternative splicing (Illingworth et al. The agouti gene encodes a peptide that stimulates production of a yellow pigment which normally is only transiently expressed in the hair follicle, producing a brown coat color. In the viable yellow agouti mouse the agouti gene contains a retrotransposon insertion with a promoter that drives ectopic expression of agouti, which results in a yellow coat color. The methylation status of the agouti gene has been demonstrated to be hypermethylated when maternal mice are supplemented with genistein (Dolinoy et al. Importantly, the agouti gene in offspring is hypomethylated when maternal mice are given bisphenol A; an effect that can be reversed by the simultaneous addition of dietary methyl donors (Dolinoy et al. The core of the nucleosome is occupied by the globular portion of the histone proteins, while the unstructured, N-terminal "tails" of the histone proteins extend freely from the nucleosome (Luger et al. Histone tails provide the location for the majority of posttranslational, covalent modifications. The core region of the nucleosome is also modified, just to a lesser extent (reviewed in Zentner and Henikoff, 2013). The number of potential modifications that can be made to each histone tail, the presence of eight tails per nucleosome, and the number of nucleosomes spanning a gene, produces high potential combinatorial complexity. For example, promoters tend to have high levels of histone 3 (H3), lysine 4 (K4) trimethylation (me3), while putative enhancers are characterized by enriched H3K4me1 alone or with H3K27acetylation (ac) or H3K27me3 (Rada-Iglesias et al. Gene bodies tend to be enriched with H3K36me2 (or me3) in association with transcriptional elongation. Acetylation of H3K9 and H3K14 appears to be a characteristic of bivalent promoters (Karmodiya et al. This renders the gene "poised" for activation upon the appropriate environmental or developmental signal (Wang et al. In addition to the combined appearance of H3K9ac and H3K14ac in bivalent promoters, inactive promoters tend to also have low levels of H3K14ac, perhaps ready for future activation (Karmodiya et al. Bottom panel: the unstructured, N-terminal "tails" of the histone proteins extend from the nucleosomes and modified with numerous covalent modifications. Environmental Exposures and Developmental Programming of the Lung 159 Methylation of histone residues also contributes to cell fate and activation of developmentally regulated genes. For example, H4K20me1 has a number of roles in the cell, can be linked to gene silencing and gene activation, as well as proliferation. H4K20me1 also contributes to the successful execution of important lung signaling pathways, including Wnt signaling (Li et al. Wnt participates as a fundamental cellular signaling pathway, regulating processes from proliferation to differentiation in alveolar formation (Pongracz and Stockley, 2006; Morrisey et al. Canonical Wnt signaling involves receptor activation by a Wnt ligand, subsequent cytoplasmic accumulation and nuclear translocation of b-catenin.

Most cross-sectional studies show more severe impairment of urinary concentrating ability in patients treated with rapidly dissolving preparations (Bendz et al heart attack high dead end counterpart digoxin 0.25 mg order visa. On the other hand blood pressure zolpidem purchase digoxin 0.25 mg fast delivery, other investigators suggest that trough serum lithium levels have a more profound influence on the severity of structural injury and renal functional impairment (Perry prehypertension food digoxin 0.25 mg sale, 1982; Perry et al arrhythmia gif cheap digoxin 0.25 mg visa. This could be explained if tubular cell regeneration occurs only during periods of low serum lithium concentrations (Hetmar et al heart attack jack heart attack discount digoxin 0.25 mg fast delivery. Multiple daily dose regimens, which achieve relatively high trough but low peak serum lithium levels, were associated with greater nephrotoxicity in several cross-sectional studies (Bowen et al. Urine volume was correlated with trough but not peak serum lithium levels (Plenge et al. A multiple daily dose lithium regimen was associated with greater urine volumes and higher serum creatinine levels than a single-dose regimen in a prospective longitudinal study extending 320 Nephrotoxicity of Lithium and Drugs of Abuse over 10 years (Hetmar et al. Other studies observed that urine volume decreased after patients were switched from a multiple-dose to a single-dose schedule of lithium treatment in the absence of differences in steady-state serum lithium levels (Hetmar et al. However, these observations must be interpreted cautiously since treatment regimens were not randomly allocated, and in some studies, the lithium dose was greater in the multiple daily dose regimen group (Hetmar et al. Moreover, other investigators failed to find any change in urine volume when patients were switched from a multiple to a single daily dose lithium treatment regimen or vice versa (Abraham et al. In addition, several cross-sectional studies failed to find a correlation between urine volume, renal concentrating ability, or renal function on the one hand and the number of lithium doses on the other (Forrest et al. These discrepant data may be reconciled in part by the observation of Kusalic and Engelsmann (1996) that conversion from multiple to single daily dosing regimen was associated with improvement in renal function only in patients who had been treated with a multiple-dosing regimen for < 5 years. In a study evaluating male patients newly started on lithium therapy, after 21 days of therapy, single daily dose regimen was associated with subjectively less urinary frequency than a multiple daily dose regimen (Singh et al. Two studies compared renal histopathology with dosing regimen and found that patients on a multiple daily dose regimen showed more severe glomerular and tubulointerstitial injury compared with those on a single daily dose regimen (Plenge et al. Similarly, two crosssectional studies of patients maintained on low-dose lithium regimens failed to find any difference in renal function compared with controls suffering from affective disorders who had never been treated with lithium (Hullin and Birch, 1979; Hullin et al. Similar results have been obtained in most uncontrolled cross-sectional studies (Bendz et al. Lithium nephrotoxicity may be exacerbated by concurrent administration of neuroleptic agents. Therapy with neuroleptic agents alone may be associated with reduced urinary concentrating ability and increased urine volume (Bucht and Wahlin, 1978, 1980; Schou and Vestergaard, 1988; Waller et al. In this regard, concurrent administration of neuroleptic agents with lithium has been associated with a more severe urinary concentrating defect, worse renal function, higher urine flow rate, and more renal histological damage compared with patients treated with lithium alone (Bakris et al. However, in several of these studies, the dose of lithium was greater in those who also received neuroleptic agents (Bucht and Wahlin, 1980; Gelenberg et al. Moreover, other investigators failed to find any difference in lithium nephrotoxicity between patients treated with lithium alone and those who also received other psychotropic agents (Hallgren et al. However, it remains to be established whether or not amiloride is capable of ameliorating long-term lithium-induced tubulointerstitial injury. The renin­angiotensin system does not appear to play an important role in mediating progressive renal injury induced by lithium, since angiotensinconverting enzyme inhibition fails to exert a beneficial effect (Skyum et al. A major role for increased oxidative stress in mediating lithium-induced nephrotoxicity has been suggested (Ahmad et al. Antioxidant and antiinflammatory agents such as caffeic acid phenethyl ester and N-acetylcysteine have been shown to have renoprotective effects in a rat model of lithium-induced nephrotoxicity (Efrati et al. Guidelines to prevent nephrotoxicity among patients treated with lithium have been promulgated by numerous organizations. Various guidelines recommend baseline determination of renal function and subsequent monitoring every 2­3 months during the first 6 months of therapy and then every 6 months to 1 year in stable patients (American Psychiatric Association, 2002) and every 3­6 months (Yatham et al. In addition, serum lithium levels should be monitored every 3 months with annual testing of urinary osmolality (National Institute for Health and Clinical Excellence, 2006). In summary, lithium-induced nephrotoxicity has little clinical consequence for most patients, especially if maintenance serum levels are kept at the lower end of the therapeutic range. However, it appears that advanced renal failure may develop in some patients on maintenance lithium therapy after decades of treatment. Since most patients treated with lithium, even long-term, do not develop significant impairment of renal function, it appears that progressive renal failure is restricted to a subgroup of patients. Identification of characteristics to distinguish this susceptible subgroup remains elusive. Moreover, data are contradictory Nephrotoxicity of Lithium and Drugs of Abuse 321 as to whether it is chronic tubulointerstitial injury or glomerular injury that is primarily responsible for the development of advanced renal failure in lithium-treated patients. Because nephrotoxicity may be associated with clinical episodes of lithium intoxication and higher serum lithium levels, an effort should be made to maintain the lowest therapeutic serum lithium level. Moreover, renal function should be monitored regularly, and the risks of nephrotoxicity for individual patients must be weighed against the therapeutic benefit from continued lithium therapy in individual patients. Subsequent cross-sectional studies of addict populations found a high prevalence of nonspecific urinary abnormalities. A specific form of focal and segmental glomerulosclerosis associated with intravenous heroin use in African Americans was first recognized in the 1970s (Rao et al. This glomerulopathy was characterized by proteinuria progressing to the nephrotic syndrome in association with progressive renal failure. At the same time, another major cause of renal failure emerged in this populationdrenal amyloidosis associated with chronic suppurative skin infections in heroin users who used the subcutaneous route (Dubrow et al. Subsequently, glomerulosclerosis in intravenous heroin users who were infected with human immunodeficiency virus was recognized as an entity distinct from heroin-associated nephropathy (Rao et al. In the past several decades, the epidemiology of nephropathy in intravenous drug abusers has changed radically. Heroin-associated focal and segmental glomerulosclerosis and secondary amyloidosis have been supplanted by human immunodeficiency virus-associated focal and segmental glomerulosclerosis and hepatitis C-related membranoproliferative glomerulonephritis (Friedman and Rao, 1995). The sharp decline and virtual disappearance of heroin-associated nephropathy in the late 20th century were attributed by Friedman and Rao (1995) to an increase in the purity of street heroin. This, these authors held, led to reduced exposure of heroin addicts to nephrotoxic adulterants. Other investigators have suggested that the high prevalence of human immunodeficiency virus infection among drug abusers was responsible for the disappearance of heroin-associated nephropathy by reducing the population of nonhuman immunodeficiency virus-infected drug addicts at risk to develop heroin-associated nephropathy (Neugarten et al. Still, others question the very existence of heroin-associated nephropathy, suggesting that unrecognized infection with human immunodeficiency virus or other viruses may have been responsible for nephropathy in these patients (Jaffe and Kimmel, 2006). Although cocaine and psychedelic drug use was also associated with renal failure, this association could not be separated from the effects of heroin use. However, the authors did not distinguish between heroin-associated nephropathy, human immunodeficiency virus-associated nephropathy, and hepatitis C-related glomerulonephritis. The confounding effects of race and demographics on the epidemiology of nephropathy in heroin users are highlighted by studies performed in European Caucasian intravenous heroin users in the late 1980s and 1990s in Dettmeyer et al. Glomerulonephritis associated with hepatitis C virus infection was the predominant lesion in this population. Although early investigators suggested that focal and segmental glomerulosclerosis in heroin users was immunologically mediated, there is little experimental evidence to support this hypothesis. Other investigators found that chronic treatment of rats and mice with morphine led to renal enlargement, proteinuria, renal insufficiency, glomerulomegaly, mesangial expansion, increased mesangial cellularity, and formation of glomerular podocyte microprojections (Arerangaiah et al. However, the administration of morphine to rats is not analogous to nonsterile injection of adulterated street heroin by addicts. In vitro studies suggest that morphine influences numerous cellular processes in a biphasic, dose-dependent manner (Hsu et al. Morphine stimulates cellular proliferation in mesangial cells, renal fibroblasts, and renal medullary interstitial cells and stimulates mesangial matrix accumulation by increasing mesangial cell collagen and laminin synthesis and suppressing collagenase activity. These effects are in part mediated by enhanced production of proproliferative and fibrogenic cytokines. Morphine also increases the accumulation of macromolecules within the glomerular mesangium and activates resident glomerular macrophages. Morphine-induced glomerular epithelial cell apoptosis is reversed by antioxidants and free radical scavengers, consistent with the observation that morphine stimulates the production of superoxide by macrophages and mesangial cells (Sharp et al. The ability of morphine to induce proliferation of cultured mesangial cells is mediated by activation of kappa opioid receptors and the signal transducer and activator of transcription 3 pathway (Weber et al. However, the relevance of these in vitro studies to human disease remains to be determined. Both endogenous and exogenous opioids have been shown to modulate renal water handling and 322 Nephrotoxicity of Lithium and Drugs of Abuse influence sodium and potassium excretion in a manner dependent on the specific peripheral opioid receptor that is activated (Mercadante and Arcuri, 2004). A clinicopathologic syndrome similar to heroin-associated nephropathy has rarely been observed in abusers of intravenous drugs other than heroin, including cocaine and pentazocine with tripelennamine (Cunningham et al. There have been rare descriptions of talc granules deposited in the arterioles and glomeruli of intravenous drug users who injected drugs compounded for oral or rectal use (Groth et al. Granulomatous interstitial nephritis with particulate deposits in the renal interstitium and glomerular deposition of lipid-like material have also been reported in intravenous drug users where the vehicle was lemon juice or a combination of acetic anhydride and sodium bicarbonate (Lynn et al. Less commonly, intravenous or oral amphetamine, methamphetamine, phencyclidine, methadone, barbiturates, and other sedatives administered alone or in combination may produce this syndrome. Phencyclidine and other stimulants may cause rhabdomyolysis by inducing involuntary muscle activity in patients confined by mechanical restraints (Barton et al. In addition, tetanus or self-injection of water has rarely been reported to give rise to rhabdomyolysis in drug users (Eknoyan et al. More recently, designer recreational drugs of abuse have increasing been identified as causative agents in nontraumatic rhabdomyolysis (Luciano and Perazella, 2014; Pendergraft et al. Most cases of heroin-associated nontraumatic rhabdomyolysis result from pressure myonecrosis and ischemic muscle injury. Extended periods of depressed consciousness and immobilization lead to prolonged pressure on dependent muscles, which in turn leads to cellular injury, tissue swelling, and vascular compromise. However, heroin-associated nontraumatic rhabdomyolysis has also been reported, albeit infrequently, in the absence of depressed consciousness or muscle compression (Gibb and Shaw, 1985; Koffler et al. In these cases, rhabdomyolysis has been attributed to a direct toxic effect of heroin on muscle or an allergic reaction to the drug or a contaminant. Generalized and symmetrical muscle swelling rather than localized muscle involvement has been observed in those cases in the absence of pressure myonecrosis (Richter et al. Consistent with a toxic or allergic pathogenesis are rare reports in which an entire extremity swells after a local injection of heroin (Richter et al. Similarly, myocarditis has been reported in association with nontraumatic rhabdomyolysis due to heroin; however, only one case of myocardial involvement has been confirmed by histology (Krige et al. These factors include hypoxia, volume depletion, acidosis, hypotension, and pyrexia (Koffler et al. Clinical evidence of muscle injury is frequently present and includes swelling and tenderness of involved muscles and localized pain and weakness. Cocaine-induced vasoconstriction may give rise to ischemic myonecrosis leading to rhabdomyolysis. In addition, cocaine has been shown to have direct toxic effects on muscle in vitro (Pagala et al. These complications include hypotension, hyperpyrexia, seizures, diffuse intravascular coagulation, and muscle compression due to prolonged immobilization. Many abused cocaine in combination with heroin or alcohol, which themselves may cause rhabdomyolysis. Moreover, cocaine may be contaminated with adulterants such as arsenic, strychnine, amphetamines, or phencyclidine, which may cause seizures and rhabdomyolysis (Crowe et al. Urinalysis characteristically shows a positive orthotolidine reaction for heme, and dipstick-positive proteinuria is frequently detected. However, it appears that this disorder usually has an excellent prognosis for renal recovery. Acute tubular necrosis has been attributed to cocaine-induced vasoconstriction (Amoedo et al. Cocaine has also been reported to cause or exacerbate scleroderma and to precipitate scleroderma renal crisis (Attoussi et al. Cocaine-induced renal artery dissection, thrombosis, or infarction has also been described (Antonovych et al. In addition, renal vein thrombosis has been described in association with cocaine use (Zoghby et al. Cocaine not only is an arterial vasoconstrictor but also may contribute to arterial thrombosis by activating platelets and increasing their aggregability, enhancing thromboxane production, and inducing endothelial cell injury. Isolated case reports have attributed a wide variety of glomerular and tubulointerstitial renal diseases to cocaine use. Cocaine use has been associated with antiglomerular basement membrane disease, acute interstitial nephritis, hyponatremia, and systemic necrotizing vasculitis (Alfaro et al. However, a causal relationship between cocaine use and many of these disorders remains to be established. Chronic administration of cocaine to rats induces glomerulosclerosis and chronic tubulointerstitial injury including tubular dilation and necrosis of tubular cells (Barroso-Moguel et al. In vitro studies of renal tissue indicate that cocaine enhances mesangial cell uptake of macromolecules, increases the release of macrophage secretory products and cytokines that stimulate mesangial cell proliferation, and is cytotoxic to proximal tubular epithelial cells (Mattana et al. Cocaine also increases cellular oxidative stress and decreases intracellular glutathione levels in renal epithelial cells (Palamara et al. However, the relationship of these experimental observations to human disease remains to be established. However, this relationship has not always been supported by epidemiological studies. These investigators concluded that cocaine use may cause an acute elevation in blood pressure but was not associated with chronic hypertension. There was no significant difference in age-adjusted blood pressure in the population of cocaine users as compared to a control group.

Furthermore blood pressure chart for 14 year old order digoxin with visa, a majority of this article outlines many of the mechanisms by which cisplatin induces kidney injury arrhythmia originating in the upper chambers of the heart generic 0.25 mg digoxin amex, including activation of cell death blood pressure medication drug classes cheapest generic digoxin uk, cell stress pulse pressure 28 digoxin 0.25 mg buy with visa, autophagy blood pressure 8560 digoxin 0.25 mg buy with mastercard, apoptosis, and inflammatory pathways. This suggests that special attention should be given to the clinical and translation relevance of models utilized to study cisplatin-induced injury in preclinical studies. Taken together, this article outlines a number of mechanisms by which chemotherapeutics induce kidney injury, and research that has been done to identify novel targets for the development of renoprotective strategies against cisplatin-induced kidney injury. Induction of heme oxygenase in toxic renal injury: A protective role in cisplatin nephrotoxicity in the rat. Renal response to tissue injury: Lessons from heme oxygenase-1 GeneAblation and expression. Protective role of selenium and high dose vitamin E against cisplatin-induced nephrotoxicity in rats. Cytochrome P450 3A and 2B6 in the developing kidney: Implications for ifosfamide nephrotoxicity. Protective effects of vitamin E and C on cisplatin nephrotoxicity in developing rats. Effects of different doses of hyperbaric oxygen on cisplatin-induced nephrotoxicity. Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces cisplatin-induced tubule injury. Renal Toxicology/Nephrotoxicity of Cisplatin and Other Chemotherapeutic Agents 481 Baliga, R. In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity. The nephrotoxic Ifosfamide-metabolite chloroacetaldehyde interferes with renal extracellular matrix homeostasis. Disturbed Ca2 þ-signaling by chloroacetaldehyde: A possible cause for chronic ifosfamide nephrotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 104, 11649­11654. Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Biomarkers for the diagnosis and risk stratification of acute kidney injury: A systematic review. Amifostine: An update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome. Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: Importance of superoxide. Biomarkers for the prediction of acute kidney injury: A narrative review on current status and future challenges. Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide. Caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis. Calpain is involved in cisplatin-induced endothelial injury in an in vitro three-dimensional blood vessel model. End-stage renal interstitial fibrosis in an adult ten years after ifosfamide therapy. Evaluation of anti-allergic activity of gossypin and suramin in mast cell-mediated allergy model. Sulforaphane, a natural constituent of broccoli, prevents cell death and inflammation in nephropathy. Gamma-glutamyl transpeptidase-deficient mice are resistant to the nephrotoxic effects of cisplatin. N-acetylcysteine rescue protocol for nephrotoxicity in children caused by ifosfamide. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. Tubulointerstitial nephritis following high-dose ifosfamide in three breast cancer patients. Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation. Cisplatin-induced apoptosis in p53-deficient renal cells via the intrinsic mitochondrial pathway. Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity. The role of pemetrexed in advanced non small-cell lung cancer: Special focus on pharmacology and mechanism of action. Role of reactive oxygen species in p53 activation during cisplatin-induced apoptosis of rat mesangial cells. Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition. Autophagy delays apoptosis in renal tubular epithelial cells in cisplatin cytotoxicity. Effect of calcium channel blockade on adrenergically induced renal vasoconstriction in rat models of renal impairment. Renal Toxicology/Nephrotoxicity of Cisplatin and Other Chemotherapeutic Agents 483 Kim, D. Beneficial effect of pentoxifylline on cisplatin-induced acute renal failure in rabbits. Proceedings of the National Academy of Sciences of the United States of America, 105, 10865­10870. Roles of cysteine conjugate beta-lyase and S-oxidase in nephrotoxicity: Studies with S-(1,2dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-L-cysteine sulfoxide. Critical subcellular targets of cisplatin and related platinum analogs in rat renal proximal tubule cells. Urinary neutrophil gelatinase-associated lipocalin levels predict cisplatin-induced acute kidney injury better than albuminuria or urinary cystatin C levels. Renal tubular Fas ligand mediates fratricide in cisplatin-induced acute kidney failure. A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity. The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats. Combining cisplatin with cationized catalase decreases nephrotoxicity while improving antitumor activity. The role of oxygen free radicals in cisplatin-induced acute renal failure in rats. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Interleukin-6 modulates oxidative stress produced during the development of cisplatin nephrotoxicity. Cisplatin reduces endothelial cell migration via regulation of type 2-matrix metalloproteinase activity. Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-alpha. Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: Reversible and chronic renal damage. Penta-O-galloyl-beta-D-glucose attenuates cisplatin-induced nephrotoxicity via reactive oxygen species reduction in renal epithelial cells and enhances antitumor activity in Caki-2 renal cancer cells. Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and amifostine. A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo. From finch to fish to man: Role of aquaporins in body fluid and brain water regulation. Mesna or cysteine prevents chloroacetaldehyde-induced cell death of human proximal tubule cells. Renal Toxicology/Nephrotoxicity of Cisplatin and Other Chemotherapeutic Agents 485 Sheikh-Hamad, D. Urinary kidney injury molecule-1 and monocyte chemotactic protein-1 are noninvasive biomarkers of cisplatin-induced nephrotoxicity in lung cancer patients. Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis. Bridging translation for acute kidney injury with better preclinical modeling of human disease. Adverse effects of anti-tumor drug, cisplatin, on rat kidney mitochondria: Disturbances in glutathione peroxidase activity. Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Inhibition of gamma-glutamyl transpeptidase or cysteine S-conjugate beta-lyase activity blocks the nephrotoxicity of cisplatin in mice. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways. Curcumin ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice. D-Ribose ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice. Urinary kidney injury molecule-1: A sensitive quantitative biomarker for early detection of kidney tubular injury. Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: A randomised, double-blind, placebo-controlled study. Reduced renal blood flow in early cisplatin-induced acute renal failure in the rat. N-acetyl S-(1,2-dichlorovinyl)-L-cysteine produces a similar toxicity to S-(1,2-dichlorovinyl)-L-cysteine in rabbit renal slices: Differential transport and metabolism. Membrane transporters and folate homeostasis: Intestinal absorption and transport into systemic compartments and tissues. As a consequence of its unique filtration, secretory and absorptive capabilities, the kidney, itself, is often exposed to higher levels of metals than most organs, and it is frequently a primary target of toxic metal injury. In light of the importance of the kidney as a target of toxic injury, considerable attention has been focused on identifying the molecular mechanisms by which metals damage the kidney and alter renal function. The problems of identifying risks and the effects of metals on the kidney, as well as mechanisms of metal toxicity, have become even more challenging because of recent advances in technology and bioengineering that have resulted in the incorporation of q Change History: October 2016. While these new nanomaterials offer tremendous potential for areas such as biosensing, tissue imaging, and targeted drug delivery, they also pose special challenges in the areas of risk assessment and mechanistic technology. In this article, we provide updates on recent findings regarding the nephrotoxicity of the metals bismuth, cadmium, chromium, indium, lead, platinum, uranium, and the metalloid arsenic on an individual and mixture basis. Bruce Fowler, who did an outstanding job in summarizing these very complex topics. Fowler has graciously granted us permission to use his previous article as a template to highlight recent advances and discuss areas for further research that have emerged in recent years. In considering the various agents, emphasis will be given to the specific mechanisms by which the various forms of the agents, including nanomaterials and mixtures, accumulate in the kidney and alter renal function. Each section includes a discussion of the mechanisms of pathophysiology as they relate to changes in the renal function and the development of renal disease. In addition, for some of the most important agents, we have included brief discussions of recent issues related to the biomonitoring of exposed populations for the early detection of nephrotoxic injury. It should be noted that, in contrast to the previous versions of this article, we have reorganized the coverage of topics based on their status as nephrotoxic agents. In prioritizing the agents, we have considered the overall hazard that they pose with respect to extent and severity of kidney injury. We have also considered the extent and quality of the research as well as the current understanding of the mechanisms of toxic injury. With the chronic low-level patterns of exposure that are common in humans, the kidney is the primary target of toxicity, where cadmium accumulates in the epithelial cells of the proximal tubule, resulting in generalized reabsorptive dysfunction characterized by polyuria and low-molecular-weight proteinuria (Jarup, 2002; Jarup and Akesson, 2009; Johri et al. However, there is also evidence to suggest that Cd-induced kidney injury can involve alterations (either increases or decreases) in glomerular function (Haswell-Elkins et al. These various renal effects can result from even relatively low levels of exposure, and children and individuals with confounding health conditions, such as diabetes, may be especially vulnerable (Akesson et al. However, authors of several recent reviews have questioned the significance of cadmium as a contributing factor to the development of kidney disease in industrial workers and the general population (Byber et al. Proximal tubular injury has been shown to occur in experimental animals and in chronically exposed human populations (either in the workplace or through the environment) (for review, see Prozialeck and Edwards, 2012).

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