Treatment with a sphingosine analog after the inception of house dust mite-induced airway inflammation alleviates key features of experimental asthma

Background

In vivo phosphorylation of sphingosine analogs with their ensuing binding and activation of their cell-surface sphingosine-1-phosphate receptors is regarded as the main immunomodulatory mechanism of this new class of drugs. Prophylactic treatment with sphingosine analogs interferes with experimental asthma by impeding the migration of dendritic cells to draining lymph nodes. However, whether these drugs can also alleviate allergic airway inflammation after its onset remains to be determined. Herein, we investigated to which extent and by which mechanisms the sphingosine analog AAL-R interferes with key features of asthma in a murine model during ongoing allergic inflammation induced by Dermatophagoides pteronyssinus.

Methods

BALB/c mice were exposed to either D. pteronyssinus or saline, intranasally, once-daily for 10 consecutive days. Mice were treated intratracheally with either AAL-R, its pre-phosphorylated form AFD-R, or the vehicle before every allergen challenge over the last four days, i.e. after the onset of allergic airway inflammation. On day 11, airway responsiveness to methacholine was measured; inflammatory cells and cytokines were quantified in the airways; and the numbers and/or viability of T cells, B cells and dendritic cells were assessed in the lungs and draining lymph nodes.

Results

AAL-R decreased airway hyperresponsiveness induced by D. pteronyssinus by nearly 70%. This was associated with a strong reduction of IL-5 and IL-13 levels in the airways and with a decreased eosinophilic response. Notably, the lung CD4⁺ T cells were almost entirely eliminated by AAL-R, which concurred with enhanced apoptosis/necrosis in that cell population. This inhibition occurred in the absence of dendritic cell number modulation in draining lymph nodes. On the other hand, the pre-phosphorylated form AFD-R, which preferentially acts on cell-surface sphingosine-1-phosphate receptors, was relatively impotent at enhancing cell death, which led to a less efficient control of T cell and eosinophil responses in the lungs.

Conclusion

Airway delivery of the non-phosphorylated sphingosine analog, but not its pre-phosphorylated counterpart, is highly efficient at controlling the local T cell response after the onset of allergic airway inflammation. The mechanism appears to involve local induction of lymphocyte apoptosis/necrosis, while mildly affecting dendritic cell and T cell accumulation in draining lymph nodes.     

Rain, breeding success and distribution of Capercaillie Tetrao urogallus and Black Grouse Tetrao tetrix in Scotland

The number of chicks reared by Capercaillie was inversely related to the number of days with rain during and just after their hatching. However, rain had no detectable effect on the breeding success of Black Grouse on the same study area. The breeding distribution of Capercaillie in Scotland is more limited than that of Black Grouse, which extends into rainier areas. It is speculated that sexual selection for large size in Capercaillie has indirectly caused their chicks to be more vulnerable to rain and, consequently, has limited their distribution to less rainy areas.     

Microsatellites reveal origin and genetic diversity of Eurasian invasions by one of the world’s most notorious marine invader,Mnemiopsis leidyi (Ctenophora)

Marine invasions are taking place at an increasing rate. When occurring in blooms, zooplanktivorous comb jellies of the genus Mnemiopsis are able to cause pelagic regime shifts in coastal areas and may cause the collapse of commercially important fish populations. Using microsatellites, developed for the first time in the phylum Ctenophora, we show that Mnemiopsis leidyi has colonized Eurasia from two source regions. Our preliminary data set included four sites within the putative source region (US East Coast and Gulf of Mexico) and 10 invaded locations in Eurasian waters. Bayesian clustering and phylogeographic approaches revealed the origin of earlier invasions of the Black and Caspian Sea in the 1980s/1990s within or close to the Gulf of Mexico, while the 2006 invasion of the North and Baltic Seas can be directly traced to New England (pairwise F_ST = 0). We found no evidence for mixing among both gene pools in the invaded areas. While the genetic diversity (allelic richness) remained similar in the Baltic Sea compared to the source region New England, it was reduced in the North Sea, supporting the view of an initial invasion of Northern Europe to a Baltic Sea port. In Black and Caspian Sea samples, we found a gradual decline in allelic richness compared to the Gulf of Mexico region, supporting a stepping‐stone model of colonization with two sequential genetic founder events. Our data also suggest that current practices of ballast water treatment are insufficient to prevent repeated invasions of gelatinous zooplankton.     

Immunolocalization of MMP-19 in the human intervertebral disc: implications for disc aging and degeneration

Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix of the disc, but the presence of MMP-19 has not been explored. In other tissues, MMP-19 is known to act in proteolysis of the insulin-like growth factor (IGF) binding protein-3, thereby exposing this protein to make it available to influence cell behavior. MMP-19 also has been shown to inhibit capillary-like formation and thus play a role in the avascular nature of the disc. Using immunohistochemistry, normal discs from six subjects aged newborn through 10 years and 20 disc specimens from control donors or surgical patients aged 15-76 (mean age 40.2 years) were examined for immunolocalization of MMP-19; six Thompson grade I discs, five Thompson grade II, eight Thompson grade III, five Thompson grade IV, and one Thompson grade V discs were analyzed. The results indicate that in discs from young subjects, MMP-19 was uniformly localized in the outer annulus. In discs from adult donors and surgical patients, outer and inner annulus cells only occasionally showed MMP-19 localization. The greatest expression of MMP-19 was observed in young discs, and little expression was seen in older or degenerating discs. Because MMP-19 has been shown to regulate IGF-mediated proliferation in other tissues, its decline in the aging/degenerating disc may contribute to the age-related decrease in disc cell numbers.     

The impact of pH on interactions among phytoplankton algae, zooplankton and perch (Perca fluviatilis) in a shallow, fertile lake

1. The combined effects of increasing pH (< 9–11) and increasing densities of perch (0, two, four per enclosure) have been investigated in polyethylene enclosures of volume about 1100 1 in a shallow, fertile lake in Cheshire. 2. Increasing pH decreased carbon dioxide concentrations, chlorophyll a concentrations and diatom biomass. It led to increases in the proportions of Cryptophyta (to pH 10) and Chlorophyta (to pH 11). Although ample inocula were present, significant growths of cyanophytes were not recorded, contrary to expectation. 3. Increasing pH led to increases in numbers of Daphnia hyalina particularly at pH 10 but collapse at pH 11. This persistence at pH 10, independent of perch number, is attributed to reduced feeding of the fish, which survived at this pH. Other zooplankters (Ceriodaphnia spp., Bosmina longirostris, Polyphemus pediculus, Cyclops spp.) all declined with increasing pH. 4. Increasing fish density resulted in an increase in chlorophyll a concentration and in the biomass of Chlorophyta but had no effect on cyanophyte or cryptophyte biomass. 5. Increasing fish density led to declines in Daphnia in the untreated lake-water controls (pH < 9) and at pH 9, but had no effect at pH 10 where Daphnia hyalina was very abundant. Numbers of Ceriodaphnia spp. and Bosmina longirostris increased with increasing fish density, whilst numbers of Polyphemus pediculus and Cyclops spp. were independent of it. 6. The results are discussed in the light of contemporary knowledge of the factors resulting in large cyanophyte growths and of the factors controlling the stability of macrophyte-dominated and phytoplankton-dominated states in shallow lakes. The interaction between pH and fish density and consequent non-linear response of Daphnia hyalina is particularly notable because of the significance of zooplankton grazing in shallow lakes.