Optimization of a transplant model to assess skin reconstitution from stem cell-enriched primary human keratinocyte populations

Given that an important functional attribute of stem cells in vivo is their ability to sustain tissue regeneration, we set out to establish a simple and easy technique to assess this property from candidate populations of human keratinocyte stem cells in an in vivo setting. Keratinocytes were inoculated into devitalized rat tracheas and transplanted subcutaneously into SCID mice, and the epithelial lining regenerated characterized to establish the validity of this heterotypic model. Furthermore, the rate and quality of epidermal tissue reconstitution obtained from freshly isolated unfractionated vs. keratinocyte stem cell-enriched populations was tested as a function of (a) cell numbers inoculated; and (b) the inclusion of irradiated support keratinocytes and dermal cells. Rapid and sustained epidermal tissue regeneration from small numbers of freshly isolated human keratinocyte stem cells validates the utilization of this simple and reliable model system to assay for enrichment of epidermal tissue-reconstituting cells.

Renal endothelial dysfunction and impaired autoregulation after ischemia-reperfusion injury result from excess nitric oxide

Endothelial dysfunction in ischemic acute renal failure (IARF) has been attributed to both direct endothelial injury and to altered endothelial nitric oxide synthase ( eNOS) activity, with either maximal upregulation of eNOS or inhibition of eNOS by excess nitric oxide ( NO) derived from iNOS. We investigated renal endothelial dysfunction in kidneys from Sprague-Dawley rats by assessing autoregulation and endothelium-dependent vasorelaxation 24 h after unilateral ( U) or bilateral ( B) renal artery occlusion for 30 (U30, B30) or 60 min (U60, B60) and in sham-operated controls. Although renal failure was induced in all degrees of ischemia, neither endothelial dysfunction nor altered facilitation of autoregulation by 75 pM angiotensin II was detected in U30, U60, or B30 kidneys. Baseline and angiotensin II-facilitated autoregulation were impaired, methacholine EC50 was increased, and endothelium-derived hyperpolarizing factor ( EDHF) activity was preserved in B60 kidneys. Increasing angiotensin II concentration restored autoregulation and increased renal vascular resistance ( RVR) in B60 kidneys; this facilitated autoregulation, and the increase in RVR was abolished by 100 mu M furosemide. Autoregulation was enhanced by N-omega-nitro-L-arginine methyl ester. Peri-ischemic inhibition of inducible NOS ameliorated renal failure but did not prevent endothelial dysfunction or impaired autoregulation. There was no significant structural injury to the afferent arterioles with ischemia. These results suggest that tubuloglomerular feedback is preserved in IARF but that excess NO and probably EDHF produce endothelial dysfunction and antagonize autoregulation. The threshold for injury-producing, detectable endothelial dysfunction was higher than for the loss of glomerular filtration rate. Arteriolar endothelial dysfunction after prolonged IARF is predominantly functional rather than structural.

Flagellin of Pseudomonas aeruginosa inhibits Na+ transport in airway epithelia

Pseudomonas aeruginosa causes severe life-threatening airway infections that are a frequent cause for hospitalization of cystic fibrosis (CF) patients. These Gram-negative pathogens possess flagella that contain the protein flagellin as a major structural component. Flagellin binds to the host cell glycolipid asialoGM1 (ASGM1), which appears enriched in luminal membranes of respiratory epithelial cells. We demonstrate that in mouse airways, luminal exposure to flagellin leads to inhibition of Na+ absorption by the epithelial Na+ channel ENaC, but does not directly induce a secretory response. Inhibition of ENaC was observed in tracheas of wild-type mice and was attenuated in mice homozygous for the frequent cystic fibrosis conductance regulator (CFTR) mutation G551D. Similar to flagellin, anti-ASGM1 antibody also inhibited ENaC. The inhibitory effects of flagellin on ENaC were attenuated by blockers of the purinergic signaling pathway, although an increase in the intracellular Ca2+ concentration by recombinant or purified flagellin or whole flagella was not observed. Because an inhibitor of the mitogen-activated protein kinase (MAPK) pathway also attenuated the effects of flagellin on Na+ absorption, we conclude that flagellin exclusively inhibits ENaC, probably due to release of ATP and activation of purinergic receptors of the P2Y subtype. Stimulation of these receptors activates the MAPK pathway, thereby leading to inhibition of ENaC. Thus, P. aeruginosa reduces Na+ absorption, which could enhance local mucociliary clearance, a mechanism that seem to be attenuated in CF.

Physiologically based synthetic models of hepatic disposition

Current Physiologically based pharmacokinetic (PBPK) models are inductive. We present an additional, different approach that is based on the synthetic rather than the inductive approach to modeling and simulation. It relies on object-oriented programming A model of the referent system in its experimental context is synthesized by assembling objects that represent components such as molecules, cells, aspects of tissue architecture, catheters, etc. The single pass perfused rat liver has been well described in evaluating hepatic drug pharmacokinetics (PK) and is the system on which we focus. In silico experiments begin with administration of objects representing actual compounds. Data are collected in a manner analogous to that in the referent PK experiments. The synthetic modeling method allows for recognition and representation of discrete event and discrete time processes, as well as heterogeneity in organization, function, and spatial effects. An application is developed for sucrose and antipyrine, administered separately and together PBPK modeling has made extensive progress in characterizing abstracted PK properties but this has also been its limitation. Now, other important questions and possible extensions emerge. How are these PK properties and the observed behaviors generated? The inherent heuristic limitations of traditional models have hindered getting meaningful, detailed answers to such questions. Synthetic models of the type described here are specifically intended to help answer such questions. Analogous to wet-lab experimental models, they retain their applicability even when broken apart into sub-components. Having and applying this new class of models along with traditional PK modeling methods is expected to increase the productivity of pharmaceutical research at all levels that make use of modeling and simulation.

Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation

Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P-450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher alpha(1)-acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.

The clinical implication of the vocal cords-carina distance in anaesthetized Chinese adults during orotracheal intubation

Background. Previous studies have identified no strong correlation between patients' height and tracheal length in anaesthetized patients. We have attempted to compare vocal cords-carina distance (VCD) in Chinese patients with the dimensions of five commonly used tracheal tubes. In addition, we attempted to find a surface anatomy measurement that would identify patients with 'short tracheas'. Methods. We measured VCD in 130 anaesthetized Chinese patients with a fibreoptic bronchoscope. Also measurements were obtained of the distal ends of five commonly used tracheal tubes. We undertook various surface anatomy measurements on the patients' chest and neck region to predict those patients with short tracheas. Results. VCD averaged 12.6 ((SD) 1.4) cm. In seven patients (5%) this distance was particularly short (between 8.8 and 10.4 cm). Many of the commonly used tracheal tubes would be placed close to or beyond the carina when the black intubation guide mark(s) is (are) at the level of the vocal cords. The VCD of

Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary hypertensive rats: comparative effects on pulmonary vascular structure and function

1 Hypoxic pulmonary hypertension in rats (10% O-2, 4 weeks) is characterized by changes in pulmonary vascular structure and function. The effects of the angiotensin converting enzyme inhibitor perindopril (oral gavage, once daily for the 4 weeks of hypoxia) on these changes were examined. 2 Perindopril (30 mg kg(-1) d(-1)) caused an 18% reduction in pulmonary artery pressure in hypoxic rats. 3 Structural changes (remodelling) in hypoxic rats included increases in (i) critical closing pressure in isolated perfused lungs (remodelling of arteries (50 mu m 0.d.) and (ii) medial wall thickness of intralobar pulmonary arteries, assessed histologically (vessels 30-100 and 101-500 mu m o.d.). Perindopril 10 and 30 mg kg(-1) d(-1) attenuated remodelling in vessels less than or equal to 100 mu m (lungs and histology), 30 mg kg(-1) d(-1) was effective in vessels 101-500 mu m but neither dose prevented hypertrophy of main pulmonary artery. 3 mg kg(-1) d(-1) was without effect. 4 Perindopril (30 mg kg(-1) d(-1)) prevented the exaggerated hypoxic pulmonary vasoconstrictor response seen in perfused lungs from hypoxic rats but did not prevent any of the functional changes (i.e. the increased contractions to 5-HT, U46619 (thromboxane-mimetic) and K+ and diminished contractions to angiotensins I and II) seen in isolated intralobar or main pulmonary arteries. Acetylcholine responses were unaltered in hypoxic rats. 5 We conclude that, in hypoxic rats, altered pulmonary vascular function is largely independent of remodelling. Hence any drug that affects only remodelling is unlikely to restore pulmonary vascular function to normal and, like perindopril, may have only a modest effect on pulmonary artery pressure.

Soft [beta]-adrenoceptor agonists for topical use in psoriasis

Psoriasis is characterised by epidermal proliferation and inflammation resulting in the appearance of elevated erythematous plaques. The ratio of c~AMP/c~GMP is decreased in psoriatic skin and when the epidermal cell surface receptors are stimulated by β-adrenergic agonists, intracellular ATP is transformed into c-AMP, thus restoring the c~AMP/c~GMP levels. This thesis describes a series of β-adrenoceptor agonists for topical delivery based upon the soft-drug approach. Soft drugs are defined as biologically active, therapeutically useful chemical compounds (drugs) characterised by a predictable and controllable In vivo destruction (metabolism) to non-toxic moieties. after they achieve their therapeutic role, The N-substituent can accommodate a broad range of structures and here the alkoxycarbonylethyl group has been used to provide metabolic susceptability. The increased polarity of the dihydroxy acid, expected after metabolic conversion of the soft~drug, ethyl N-[2'-(3',4'-dihydroxyphenyl)-2'-hydroxyethyl]-3- aminopropionate, should eliminate agonist activity. Further. to prevent oxidation and enhance topical delivery, the catechol hydroxyl groups have been esterified to produce a pro-soft-drug which generates the soft-drug in enzymic systems. The chemical hydrolysis of the pro-soft-drug proceeded via the formation of the dlpivaloyloxy acid and it failed to generate the active dihydroxy ester soft-drug. In contrast, in the presence of porcine liver carboxyesterase, the hydrolysis of the pro-soft drug proceeded via the formation of the required active soft-drug. This compound, thus, has the appropnate kinetic features to enable it to be evaluated further as a drug for the treatment of psoriasis. The pH rate-profile for the hydrolysis of soft-drug indicated a maximum stability at pH ∼ 4.0. The individual rate constants for the degradation and the pKa were analysed by nonlinear regression. The pKa of 7.40 is in excellent agreement with that determined by direct titration (7.43) and indicates that satisfactory convergence was achieved. The soft-drug was poorly transported across a silicone membrane; it was also air-sensitive due to oxidation of the catechol group. The transport of the pro-soft-drug was more efficient and, over the donor pH range 3-8, increased with pH. At lower values, the largely protonated species was not transported. However, above pH 7. chemical degradation was rapid so that a donor pH of 5-6 was optimum. The β-adrenergic agonist activity of these compounds was tested in vitro by measuring chronotropic and inotropic responses in the guinea pig atria and relaxation of guinea pig trachea precontracted with acetylcholine (10-3 M). The soft~drug was a full agonist on the tracheal preparation but was less potent than isoprenaline. Responses of the soft~drug were competitively antagonised by propranolol (10-6 M). The soft~drug produced an increase in force and rate of the isolated atrial preparatIon. The propyl analogue was equally potent with ED50 of 6.52 x 10-7 M. In contrast, at equivalent doses, the dihydroxy acid showed no activity; only a marginal effect was observed on the tracheal preparation. For the pro~soft-drug, responses were of slow onset, in both preparations, with a slowly developing relaxatlon of the tracheal preparatlon at high concentrations (10-5 M). This is consistent with in vitro results where the dipivaloyl groups are hydrolysed more readily than the ethyl ester to gIve the active soft-drug. These results confirm the validity tif the pro-soft-drug approach to the deUvery of β-adrenoceptor agonists.

Citoarquitetura e imunoistoquímica para tirosinahidroxilase dos núcleos dopaminérgicos mesencefálicos do morcego (Artibeus planirostris)

The 3-Hidroxytyramine/dopamine (DA) is a monoamine of catecholamine family and isthe precursor substance synthesis of noradrenaline and adrenaline, having the enzymeTyrosine Hydroxylase (TH) as this regulatory process. In addition, the DA has theability to act as a neurotransmitter in the Central Nervous System - SNC, being themain neurotransmitter of brain nuclei, namely of A8 to A16. The nuclei of the midbrainthat express DA are the Retrorubral Field (RRF, A8), the Substantia Nigra parsCompacta (SNc, A9) and the Ventral Tegmental Area (VTA, A10). Such nuclei areinvolved in complex three circuitry that are the mesostriatal, mesolimbic andmesocotical and are directly related with several behavioral manifestations as motricitycontrol, reward signaling in behavioral learning, motivation and pathologicalconditions, such as Parkinson's Disease and schizophrenia. Interestingly, many of themorphological bases of these neural disturbance remain unknown. Considering therelevance of mesencephalic dopaminergic nuclei, the aim of this research is tocharacterize morphologically the dopaminergic nuclei (clusters A8, A9 and A10) of themidbrain of the bat (Artibeus planirostris). The Artibeus planirostris is a common bat inRio Grande do Norte. Ten animals were used in this research. The animals wereanesthetized, perfused, and the brain was removed from the skull. After dehydration insucrose, the brain was underwent microtomy. Saggital and coronal sections wereobtained and collected in six separate series. The series were Nissl-stained to identifythe cytoarchitectonic boundaries and the other series were subjected toimmunohistochemistry for TH. After cytoarchitectonic analysis and TH+ cellsidentification was possible to establish the anatomical boundaries of the nuclei, as wellas the subdivisions of three of the midbrain dopaminergic nuclei. The SNc is the mostrostral nucleus observed in the midbrain and is identified throughout the rostrocaudalextension of the midbrain. The VTA neurons were seen immediately caudal to the SNcappearance. The RRF neurons were observed just in the caudal levels of the midbrain.The SNc in Artibeus planirostris shows a particular feature, the tail of the SNc. The tailhave been described just in two other studied species. The present work shows aparticular variation in the organizational morphology of the SNc in the artibeus andcontribute to understand the phylogenetic routes by which the dopaminergic system hasevolved.

Organização nuclear do sistema serotonérgico no encéfalo de morcegos Artibeus planirostris

Serotonin or 5-hydroxytryptamine (5-HT) is a substance found in many tissues of the body, including the nervous system acting as a neurotransmitter. Within the neuro-axis, the location of the majority of the 5-HT neurons is superimposed with raphe nuclei of the brain stem, in the median line or its vicinity, so that neuronal 5-HT can be considered a marker of the raphe nuclei. Serotonergic neurons are projected to almost all areas of the brain. Studies show the participation of serotonin in regulating the temperature, feeding behavior, sexual behavior, biological rhythms, sleep, locomotor function, learning, among others. The anatomy of these groups has been revised in many species, including mouse, rabbit, cat and primates, but never before in a bat species from South America. This study aimed to characterize the serotonergic clusters in the brain of the bat Artibeus planirostris through immunohistochemistry for serotonin. Seven adult bat males of Artibeus planirostris species (Microchiroptera, Mammalia) were used in this study. The animals were anesthetized, transcardially perfused and their brains were removed. Coronal sections of the frozen brain of bats were obtained in sliding microtome and subjected to immunohistochemistry for 5-HT. Delimit the caudal linear (CLi), dorsal (DR), median (MnR), paramedian (PMnR), pontine (PNR), magnus (MgR), pallidus (RPA) and obscurus (ROb) raphe nucleus, in addition to the groups B9 and rostral and caudal ventrolateral (RVL/CVL). The serotonergic groups of this kind of cheiroptera present morphology and cytoarchitecture relatively similar to that described in rodents and primates, confirming the phylogenetic stability of these cell clusters.

Effet du CP-3(iv), un ligand du récepteur CD36, sur le stress oxydatif suite à une ischémie cardiaque transitoire chez la souris

Le récepteur éboueur CD36 facilite l’internalisation des acides gras libres non estérifiés (AGNE) au niveau des tissus cardiaque et périphériques. Lors d’une ischémie-reperfusion du myocarde (MI/R), les dommages produits sont en partie liés à l’internalisation des AGNE et à la production d’espèces réactives de l’oxygène, contrairement à ce qui est observé chez des souris déficientes en CD36 (CD36-/-). Nous avons émis l’hypothèse selon laquelle le CP-3(iv), un ligand synthétique du récepteur CD36, exercerait un effet cardioprotecteur en réduisant la taille de la zone myocardique infarcie lors d’une ischémie transitoire du myocarde. Nos objectifs étaient 1) de déterminer l’effet cardioprotecteur du CP-3(iv) et 2) de définir son mécanisme. Pour cela, des études in vivo et ex vivo ont été faites. Des souris de type sauvage ont été traitées avec le CP-3(iv) (289 nmol/kg) par voie sous-cutanée pendant 14 jours avant d’être soumises à 30 minutes d’ischémie suivant la ligature de l’artère coronaire gauche descendante et de sa reperfusion pendant une période de 6 ou 48 heures. De plus, des coeurs isolés de souris ont été perfusés 30 minutes, suivi de 40 minutes à faible débit (10%) et de 30 minutes de reperfusion pendant laquelle le coeur est perfusé avec le CP-3(iv) à une concentration de 10-6 M. Nos travaux ont montré que l’effet cardioprotecteur d’un traitement préventif par le CP-3(iv) permet de diminuer la taille de l’infarctus et préserve l’hémodynamie cardiaque de façon dépendante du CD36 puisque cet effet est non visible chez les souris CD36-/-. De plus, le CP-3(iv) exerce non seulement un effet systémique, mais aussi un effet cardioprotecteur direct sur le coeur isolé.

On the Advancement of Probabilistic Models of Decompression Sickness

The work presented in this dissertation is focused on applying engineering methods to develop and explore probabilistic survival models for the prediction of decompression sickness in US NAVY divers. Mathematical modeling, computational model development, and numerical optimization techniques were employed to formulate and evaluate the predictive quality of models fitted to empirical data. In Chapters 1 and 2 we present general background information relevant to the development of probabilistic models applied to predicting the incidence of decompression sickness. The remainder of the dissertation introduces techniques developed in an effort to improve the predictive quality of probabilistic decompression models and to reduce the difficulty of model parameter optimization.

The first project explored seventeen variations of the hazard function using a well-perfused parallel compartment model. Models were parametrically optimized using the maximum likelihood technique. Model performance was evaluated using both classical statistical methods and model selection techniques based on information theory. Optimized model parameters were overall similar to those of previously published Results indicated that a novel hazard function definition that included both ambient pressure scaling and individually fitted compartment exponent scaling terms.

We developed ten pharmacokinetic compartmental models that included explicit delay mechanics to determine if predictive quality could be improved through the inclusion of material transfer lags. A fitted discrete delay parameter augmented the inflow to the compartment systems from the environment. Based on the observation that symptoms are often reported after risk accumulation begins for many of our models, we hypothesized that the inclusion of delays might improve correlation between the model predictions and observed data. Model selection techniques identified two models as having the best overall performance, but comparison to the best performing model without delay and model selection using our best identified no delay pharmacokinetic model both indicated that the delay mechanism was not statistically justified and did not substantially improve model predictions.

Our final investigation explored parameter bounding techniques to identify parameter regions for which statistical model failure will not occur. When a model predicts a no probability of a diver experiencing decompression sickness for an exposure that is known to produce symptoms, statistical model failure occurs. Using a metric related to the instantaneous risk, we successfully identify regions where model failure will not occur and identify the boundaries of the region using a root bounding technique. Several models are used to demonstrate the techniques, which may be employed to reduce the difficulty of model optimization for future investigations.

Open-source virtual bronchoscopy for image guided navigation

This thesis describes the development of an open-source system for virtual bronchoscopy used in combination with electromagnetic instrument tracking. The end application is virtual navigation of the lung for biopsy of early stage cancer nodules. The open-source platform 3D Slicer was used for creating freely available algorithms for virtual bronchscopy. Firstly, the development of an open-source semi-automatic algorithm for prediction of solitary pulmonary nodule malignancy is presented. This approach may help the physician decide whether to proceed with biopsy of the nodule. The user-selected nodule is segmented in order to extract radiological characteristics (i.e., size, location, edge smoothness, calcification presence, cavity wall thickness) which are combined with patient information to calculate likelihood of malignancy. The overall accuracy of the algorithm is shown to be high compared to independent experts' assessment of malignancy. The algorithm is also compared with two different predictors, and our approach is shown to provide the best overall prediction accuracy. The development of an airway segmentation algorithm which extracts the airway tree from surrounding structures on chest Computed Tomography (CT) images is then described. This represents the first fundamental step toward the creation of a virtual bronchoscopy system. Clinical and ex-vivo images are used to evaluate performance of the algorithm. Different CT scan parameters are investigated and parameters for successful airway segmentation are optimized. Slice thickness is the most affecting parameter, while variation of reconstruction kernel and radiation dose is shown to be less critical. Airway segmentation is used to create a 3D rendered model of the airway tree for virtual navigation. Finally, the first open-source virtual bronchoscopy system was combined with electromagnetic tracking of the bronchoscope for the development of a GPS-like system for navigating within the lungs. Tools for pre-procedural planning and for helping with navigation are provided. Registration between the lungs of the patient and the virtually reconstructed airway tree is achieved using a landmark-based approach. In an attempt to reduce difficulties with registration errors, we also implemented a landmark-free registration method based on a balanced airway survey. In-vitro and in-vivo testing showed good accuracy for this registration approach. The centreline of the 3D airway model is extracted and used to compensate for possible registration errors. Tools are provided to select a target for biopsy on the patient CT image, and pathways from the trachea towards the selected targets are automatically created. The pathways guide the physician during navigation, while distance to target information is updated in real-time and presented to the user. During navigation, video from the bronchoscope is streamed and presented to the physician next to the 3D rendered image. The electromagnetic tracking is implemented with 5 DOF sensing that does not provide roll rotation information. An intensity-based image registration approach is implemented to rotate the virtual image according to the bronchoscope's rotations. The virtual bronchoscopy system is shown to be easy to use and accurate in replicating the clinical setting, as demonstrated in the pre-clinical environment of a breathing lung method. Animal studies were performed to evaluate the overall system performance.

Novel ketone diet enhances physical and cognitive performance

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [(31)P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.

The complexity of Drosophila innate immunity

Metazoans rely on efficient mechanisms to oppose infections caused by pathogens. The immediate and first-line defense mechanism(s) in metazoans, referred to as the innate immune system, is initiated upon recognition of microbial intruders by germline encoded receptors and is executed by a set of rapid effector mechanisms. Adaptive immunity is restricted to vertebrate species and it is controlled and assisted by the innate immune system. Interestingly, most of the basic signaling cascades that regulate the primeval innate defense mechanism(s) have been well conserved during evolution, for instance between humans and the fruit fly, Drosophila melanogaster. Being devoid of adaptive signaling and effector systems, Drosophila has become an established model system for studying pristine innate immune cascades and reactions. In general, an immune response is evoked when microorganisms pass the fruit fly’s physical barriers (e.g. cuticle, epithelial lining of gut and trachea), and it is mainly executed in the hemolymph, the equivalent of the mammalian blood. Innate immunity in the fruit fly consists of a phenoloxidase (PO) response, a cellular response (hemocytes), an antiviral response, and the NF-κB dependent production of antimicrobial peptides referred to as the humoral response. The JAK/STAT and Jun kinase signaling cascades are also implicated in the defence against pathogens.