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PubMed1997

Bowditch lecture. Integrated regulation of intestinal epithelial transport: intercellular and intracellular pathways.

The intestinal epithelium is an important site of active solute transport processes. Such processes include the secretion of electrolytes into the lumen, predominantly chloride and bicarbonate. These secretory mechanisms subserve a variety of functions, both physiological and pathophysiological, including maintenance of the fluidity of intestinal contents and mucosal defense. Both chloride and bicarbonate secretion are the subject of integrated regulatory mechanisms at both the intercellular and intracellular levels. The goal of this article is to discuss data that exemplify these two levels of regulation, which have been the subject of research in my laboratory. It is likely that some of these principles are also broadly applicable to secretory epithelial cells outside of the intestinal tract, such as those in the airway. I also discuss the ways in which we believe these regulatory mechanisms are involved not only in intestinal physiology but also perhaps in the pathogenesis of specific disease states.

Animals↗
PubMed2003

How can we battle the scourge of diarrhea? 2003 McKenna Memorial Lecture.

Diarrheal diseases exact a considerable toll of morbidity and mortality worldwide, including in developed countries where the incidence of foodborne illness, in particular, may be increasing. This article summarizes the current understanding of the basis of diarrheal illness, focusing particularly on intracellular signaling mechanisms that limit the extent of intestinal epithelial chloride secretion, which may offer new targets for antidiarrheal therapies. Recent information regarding the mechanisms whereby invasive bacteria cause diarrhea is also reviewed along with effects of beneficial bacteria (so-called probiotics) in limiting dysfunction associated with enteric infections. Finally, the author provides some speculations as to the possible benefits to the host of mounting a diarrheal response to an offending pathogen, and possible consequences of the failure of this primitive host defense mechanism.

Diarrhea↗
PubMed2001

Albert Renold memorial lecture: molecular background of nutritionally induced insulin resistance leading to type 2 diabetes--from animal models to humans.

Albert Renold strived to gain insight into the abnormalities of human diabetes by defining the pathophysiology of the disease peculiar to a given animal. He investigated the Israeli desert-derived spiny mice (Acomys cahirinus), which became obese on fat-rich seed diet. After a few months hyperplasia and hypertrophy of beta-cells occurred leading to a sudden rupture, insulin loss and ketosis. Spiny mice were low insulin responders, which is probably a characteristic of certain desert animals, protecting against insulin oversecretion when placed on an abundant diet. We have compared the response to overstimulation of several mutant diabetic species and nutritionally induced nonmutant animals when placed on affluent diet. Some endowed with resilient beta-cells sustain long-lasting oversecretion, compensating for the insulin resistance, without lapsing into overt diabetes. Some with labile beta cells exhibit apoptosis and lose their capacity of coping with insulin resistance after a relatively short period. The wide spectrum of response to insulin resistance among different diabetes prone species seems to represent the varying response of human beta cells among the populations. In search for the molecular background of insulin resistance resulting from overnutrition we have studied the Israeli desert gerbil Psammomys obesus (sand rat), which progresses through hyperinsulinemia, followed by hyperglycemia and irreversible beta cell loss. Insulin resistance was found to be the outcome of reduced activation of muscle insulin receptor tyrosine kinase by insulin, in association with diminished GLUT4 protein and DNA content and overexpression of PKC isoenzymes, notably of PKCepsilon. This overexpression and translocation to the membrane was discernible even prior to hyperinsulinemia and may reflect the propensity to diabetes in nondiabetic species and represent a marker for preventive action. By promoting the phosphorylation of serine/threonine residues on certain proteins of the insulin signaling pathway, PKCepsilon exerts a negative feedback on insulin action. PKCepsilon was also found to attenuate the activity of PKB and to promote the degradation of insulin receptor, as determined by co-incubation in HEK 293 cells. PKCepsilon overexpression was related to the rise in muscle diacylglycerol and lipid content, which are prevalent on lascivious nutrition especially if fat-rich. Thus, Psammomys illustrates the probable antecedents of the development of worldwide diabetes epidemic in human populations emerging from food scarcity to nutritional affluence, inappriopriate to their metabolic capacity.

Animal Nutritional Physiological Phenomena↗
PubMed1999

Diagnostic approach of phospholipid-dependent antibodies. State-of-the art lecture.

Recent scientific developments enable to better understand the strong heterogeneity of assay methods for phospholipid (PLP)-dependent antibodies, measured as lupus anticoagulant (LA) or as anti-PLP antibodies (APA). These latter are actually targeted at complexes of beta(2)-glycoprotein I (beta2GPI) and anionic PLP and also react with insolubilized beta2GPI alone in some patients. Although APA present little species specificity for beta2GPI, some of them bind preferentially to complexes of human beta2GPI and PLP. LAs are diagnosed with screening assays (dPT, dRVVT, KCT, APTT); their sensitivity is dependent on the concentration and type of PLPs used. They are either beta2GPI or prothrombin dependent. Based on the antibody-neutralizing capacity of PLP preparations (such as hexagonal phase phosphatidylethanolamine) or their bypassing activity, confirmatory assays enable to confirm LA. LAs and APAs bind to different epitopes on beta2GPI or its complexes with PLP. Major characteristics of APA assays are: the capture antigen (PLPs, beta2GPI source); its optimization and density on micro-ELISA plates; the efficacy of postcoating saturation; the animal serum used for saturation and diluent; the second antibody which must avoid nonspecific interactions; the calibrators proposed and their reference to international standards; the cutoff between the normal and the pathological ranges; the assay sensitivity and overall specificity for APAs. New optimized assays have been developed to meet these criteria. They are designed with PLP-coated plates, saturated first with immunoglobulin-free human serum as a source of beta2GPI, then with goat serum also used in diluent. The cutoff value is determined with at least 200 normal plasma samples (mean + 3 standard deviations or 99th percentiles) and plasma samples from patients without APAs. This approach offers both optimized specificity and sensitivity for testing APAs, along with a good standardization and it helps to measure the true APAs associated with pathology.

Antibodies, Antiphospholipid↗
PubMed1999

Distinguished Scientists Lecture Series. New developments in kidney development.

BACKGROUND/AIMS: The number of kidney transplantations performed per year is limited due to the availability of donor organs. One possible solution to the organ shortage is the use of renal xenografts. However, the transplantation of xenografts is complicated by rejection. METHODS: It has been postulated that the host immune response might be attenuated following the transplantation of embryonic kidneys (metanephroi) rather than developed (adult kidneys). Transplanted metanephroi become chimeric organs in that their blood supply originates from the host. It is possible to transplant a developing metanephros, without the use of immunosuppression, from one outbred rat to another. RESULTS: Transplanted metanephroi grow, develop, become vascularized, and function in host rats. In contrast, developed adult kidneys transplanted from one rat to another undergo rejection within 7 days after transplantation. CONCLUSIONS: These observations suggest that metanephric tissue may be less immunogenic than adult kidney. Transplantation of metanephroi represents a new development that could lead to a novel therapeutic approach to the treatment of chronic renal failure.

Animals↗
PubMed1999

Distinguished Scientists Lecture Series. HIV-associated nephropathy.

HIV-associated nephropathy is manifested by heavy proteinuria and renal insufficiency and characterized pathologically by the collapsing variant of focal and segmental glomerulosclerosis with acute tubular necrosis and mild interstitial inflammation. Untreated, it may result in end-stage renal disease in as little as 4 months. It may present in patients with any manifestation of HIV infection, and affects predominantly black individuals. Insights into pathogenesis have come from a transgenic mouse model, renal cell cultures, and from study of human biopsy material. Although the pathogenesis is not completely understood, current considerations revolve around the role of HIV or protein in renal epithelium and the effects of cytokines, including transforming growth factor-beta and basic fibroblast growth factor, on renal structures. Therapy with zidovudine, corticosteroids, or angiotensin-converting enzyme inhibitors has met with modest success; to date, protease inhibitors have not been assessed.

AIDS-Associated Nephropathy↗
PubMedDate not supplied

Invited lecture: activation of the epithelial mesenchymal trophic unit in the pathogenesis of asthma.

BACKGROUND: A recent NIH Workshop and an ERS Task Force concluded that more work was needed to understand mechanisms of severe and chronic asthma. This report describes a series of studies that identify aberrant epithelial mesenchymal signalling in the airways as an important event in maintaining inflammation and driving remodelling in response to environmental injury. METHODS: Immunohistochemistry, genotyping and functional studies conducted on cultured asthmatic cells and mucosal biopsies were used to identify biochemical pathways involved in epithelial injury and repair in asthma and their relationship to disease severity. RESULTS: Our findings suggest that the asthmatic state results from an interaction between a susceptible epithelium and Th-2-mediated inflammation to alter the communication between the epithelium and the underlying mesenchyme - the epithelial mesenchymal trophic unit - leading to disease persistence, airway remodelling and refractoriness to corticosteroid treatment. CONCLUSIONS: Asthma is more than an inflammatory disorder, but requires engagement of important signalling pathways involved in epithelial repair and tissue remodelling. These pathways involving EGFRs and TGF-betaRs provide targets against which to develop novel therapies for chronic asthma.

Asthma↗
PubMed2002

Lung lining liquid - the hidden depths. The 5th Nils W. Svenningsen memorial lecture.

The volume of liquid which lines the lumen of the lung is small and thus exists as an extremely thin layer. Nevertheless, it appears to have important functions which include contributing to the mechanical and chemical defences of the pulmonary epithelium and providing the correct ionic environment for surfactant function. Energy is expended by the epithelium to prevent excess liquid accumulating, a process involving active transport of sodium ions out of the lumen. Precisely how lung lining liquid (LLL) is formed and how its volume is controlled remain uncertain. Control of volume is important to prevent excess liquid interfering with gas exchange: yet too little liquid would inhibit efficient functioning of the airway ciliary escalator and thus removal of mucus, debris and pathogens. The chemical content of LLL is also controlled by the epithelium. LLL pH is acidic which favours calcium ionisation, important for surfactant function. Glucose is removed from LLL so decreasing the likelihood of bacterial growth and reducing extra-cellular glycosylation of proteins such as immunoglobulins and surfactant apoproteins which would destroy their function. LLL is rich in antioxidant species, protecting the lung from atmospheric oxygen and free radicals formed by inflammation. The physico-chemical properties of water itself may be important when the lining layer is very thin. The structure of water can be semi-crystalline under some circumstances which could impart another role to LLL - that of contributing to the structural integrity of the surfactant/LLL/epithelial complex.

Animals↗