Translational research : the journal of laboratory and clinical medicine
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Review Comparative Study
Porcine models of digestive disease: the future of large animal translational research.
There is increasing interest in nonrodent translational models for the study of human disease. The pig, in particular, serves as a useful animal model for the study of pathophysiological conditions relevant to the human intestine. This review assesses currently used porcine models of gastrointestinal physiology and disease and provides a rationale for the use of these models for future translational studies. ⋯ Pigs have also shown great promise for the study of intestinal barrier function, surgical tissue manipulation and intervention, as well as biomaterial implantation and tissue transplantation. Advantages of pig models highlighted by these studies include the physiological similarity to human intestine and mechanisms of human disease. Emerging future directions for porcine models of human disease include the fields of transgenics and stem cell biology, with exciting implications for regenerative medicine.
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Vestibular schwannomas (VSs) are the most common tumors of the cerebellopontine angle. Significant clinical need exists for pharmacotherapies against VSs. Motivated by previous findings that immunohistochemical expression of cyclooxygenase 2 (COX-2) correlates with VS growth rate, we investigated the role of COX-2 in VSs and tested COX-2 inhibiting salicylates against VSs. ⋯ These drugs neither increased VS cell death nor affected healthy SCs. The cytostatic effect of aspirin in vitro was in concurrence with our previous clinical finding that patients with VS taking aspirin demonstrate reduced tumor growth. Overall, this work suggests that COX-2 is a key modulator in VS cell proliferation and survival and highlights salicylates as promising pharmacotherapies against VS.
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The role of ion channels is largely unknown in chemokine-induced migration in nonexcitable cells such as dendritic cells (DCs). Here, we examined the role of intermediate-conductance calcium-activated potassium channel (KCa3.1) and chloride channel (CLC3) in lymphatic chemokine-induced migration of DCs. The amplitude and kinetics of chemokine ligand (CCL19/CCL21)-induced Ca(2+) influx were associated with chemokine receptor 7 expression levels, extracellular-free Ca(2+) and Cl(-), and independent of extracellular K(+). ⋯ Blockade of KCa3.1, low Cl(-) in the medium, and low dose of 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) impaired CCL19/CCL21-induced Ca(2+) influx, cell volume change, and DC migration. High doses of DIDS completely blocked DC migration possibly by significantly disrupting mitochondrial membrane potential. In conclusion, KCa3.1 and CLC3 are critical in human DC migration by synergistically regulating membrane potential, chemokine-induced Ca(2+) influx, and cell volume.
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Increasing evidence indicated that excess salt consumption can impose risks on human health and a reduction in daily salt intake from the current average of approximately 12 g/d to 5-6 g/d was suggested by public health authorities. The studies on mice have revealed that sodium chloride plays a role in the modulation of the immune system and a high-salt diet can promote tissue inflammation and autoimmune disease. However, translational evidence of dietary salt on human immunity is scarce. ⋯ The results showed that subjects on the high-salt diet of 12 g/d displayed a significantly higher number of immune cell monocytes compared with the same subjects on a lower-salt diet, and correlation test revealed a strong positive association between salt-intake levels and monocyte numbers. The decrease in salt intake was accompanied by reduced production of proinflammatory cytokines interleukin (IL)-6 and IL-23, along with enhanced producing ability of anti-inflammatory cytokine IL-10. These results suggest that in healthy humans high-salt diet has a potential to bring about excessive immune response, which can be damaging to immune homeostasis, and a reduction in habitual dietary salt intake may induce potentially beneficial immune alterations.
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Agriculture industry workers are at a higher risk for chronic bronchitis and obstructive pulmonary diseases, and current therapeutics are not entirely effective. We previously found that the specialized proresolving lipid mediator maresin-1 (MaR1) reduced proinflammatory cytokine release and intracellular adhesion molecule-1 (ICAM-1) expression in bronchial epithelial cells exposed to extracts of organic dust (DE) derived from swine confinement facilities in vitro. The objective of this study was to determine whether MaR1 is effective at limiting lung inflammation associated with acute and repetitive exposures to DE in an established murine model of inhalant dust exposures. ⋯ In both single and repetitive DE exposure studies, MaR1 significantly decreased bronchoalveolar lavage neutrophil infiltration, interleukin 6, tumor necrosis factor α, and chemokine C-X-C motif ligand 1 levels without altering repetitive DE-induced bronchioalveolar inflammation or lymphoid aggregate formation. Lung tissue ICAM-1 expression was also reduced in both single and repetitive exposure studies. These data suggest that MaR1 might contribute to an effective strategy to reduce airway inflammatory diseases induced by agricultural-related organic dust environmental exposures.