Deleterious effects of indomethacin in the mid-gestation human intestine.

The use of the anti-inflammatory drug indomethacin (INDO) in preterm infants has been associated with an increased risk of developing enteropathies. In this study, we have investigated the direct impact of INDO on the human mid-gestation intestinal transcriptome using serum-free organ culture. After determining the optimal dose of 1 µM of INDO (90% inhibition of intestinal prostaglandin E2 production and range of circulating levels in treated preterm babies), global gene expression profiles were determined using Illumina bead chip microarrays in both small and large intestines after 48 h of INDO treatment. Using Ingenuity Pathway Analysis software, we identified critical metabolic pathways that were significantly altered by INDO in both intestinal segments including inflammation and also glycolysis, oxidative phosphorylation and free radical scavenging/oxidoreductase activity, which were confirmed by qPCR at the level of individual genes. Taken together, these data revealed that INDO directly exerts multiple detrimental effects on the immature human intestine.

Anti-inflammatory effects of epidermal growth factor on the immature human intestine.

The inflammatory response of the preterm infants' intestine underlines its inability to respond to hemodynamic stress, microbes, and nutrients. Recent evidence suggests that exogenous epidermal growth factor (EGF) exerts a therapeutic influence on neonatal enteropathies. However, the molecular mechanisms underlying the beneficial effects of EGF remain to be clarified. The purpose of this study was to evaluate the impact of EGF on the gene expression profiles of the developing human small and large intestine at midgestation in serum-free organ cultures using microarrays. The gene expression profiles of cultured human fetal ileal and colonic explants were investigated in the absence or presence of a physiological concentration of 50 ng/ml EGF for 48 h. Data were analyzed with the Ingenuity Pathway Analysis (IPA) software and confirmed by qPCR. We found a total of 6,474 differentially expressed genes in the two segments in response to EGF. IPA functional analysis revealed that in addition to differentially modulating distinct cellular, molecular, and physiological functions in the small and large intestine, EGF regulated the inflammatory response in both intestinal segments in a distinct manner. For instance, several intestinal-derived chemokines such as CCL2, CCL25, CXCL5, and CXCL10 were found to be differentially regulated by EGF in the immature ileum and colon. The findings showing the anti-inflammatory influence of exogenous EGF suggests a mechanistic basis for the beneficial effects of EGF on neonatal enteropathies. These results reinforce growing evidence that by midgestation, the human small intestine and colon rely on specific and distinct regulatory pathways.

Outdoor weathering and dissolution of TNT and Tritonal.

Low-order detonations of military munitions scatter cm-sized chunks of high-explosives onto military range soils, where rainfall can dissolve and then transport the explosives to groundwater. We present 1 year of mass-loss data obtained from cm-sized chunks of the frequently used explosives TNT (2,4,6-trinitrotoluene) and Tritonal (an 80:20 mixture of TNT and aluminum flakes) exposed outdoors to weather and dissolve under natural conditions. The explosive chunks rested on glass frits in individual funnels and all precipitation interacting with them was collected and analyzed. Mass balance data reveal that TNT in the water samples accounts for only about one-third of the TNT lost from the chunks. The creation of photo-transformation products on the solid chunks, and their subsequent dissolution or sublimation, probably accounts for the other two-thirds. Although these products cannot, as yet, be quantified they are intrinsic to the outdoor weathering and fate of TNT-based explosives. TNT in our water samples was not photo-transformed. Thus, we used the yearlong, dissolved-mass time-series to validate a drop-impingement dissolution model for TNT. The model used measured rainfall and air temperature data as input, and the results agreed remarkably well with TNT dissolved-mass time-series measured for the year. This model can estimate annual TNT influx into range soils using annual rainfall and particle-size distributions. Nevertheless, large uncertainties remain in the numbers and sizes of TNT particles scattered on military ranges and the identities and fates of the photo-transformation products.

Simulated rainfall-driven dissolution of TNT, Tritonal, Comp B and Octol particles.

Live-fire military training can deposit millimeter-sized particles of high explosives (HE) on surface soils when rounds do not explode as intended. Rainfall-driven dissolution of the particles then begins a process whereby aqueous HE solutions can enter the soil and groundwater as contaminants. We dripped water onto individual particles of TNT, Tritonal, Comp B and Octol to simulate how surface-deposited HE particles might dissolve under the action of rainfall and to use the data to verify a model that predicts HE dissolution as a function of particle size, particle composition and rainfall rate. Particle masses ranged from 1.1 to 17 mg and drip rates corresponded to nominal rainfall rates of 6 and 12 mmh(-1). For the TNT and Tritonal particles, TNT solubility governed dissolution time scales, whereas the lower-solubility of RDX controlled the dissolution time of both RDX and TNT in Comp B. The large, low-solubility crystals of HMX slowed but did not control the dissolution of TNT in Octol. Predictions from a drop-impingement dissolution model agree well with dissolved-mass timeseries for TNT, Tritonal and Comp B, providing some confidence that the model will also work well when applied to the rainfall-driven, outdoor dissolution of these HE particles.