Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4.

Pulmonary fibrosis is a progressive, dysregulated response to injury culminating in compromised lung function due to excess extracellular matrix production. The heparan sulfate proteoglycan syndecan-4 is important in mediating fibroblast-matrix interactions, but its role in pulmonary fibrosis has not been explored. To investigate this issue, we used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis. We found that bleomycin treatment increased syndecan-4 expression. Moreover, we observed a marked decrease in neutrophil recruitment and an increase in both myofibroblast recruitment and interstitial fibrosis in bleomycin-treated syndecan-4-null (Sdc4-/-) mice. Subsequently, we identified a direct interaction between CXCL10, an antifibrotic chemokine, and syndecan-4 that inhibited primary lung fibroblast migration during fibrosis; mutation of the heparin-binding domain, but not the CXCR3 domain, of CXCL10 diminished this effect. Similarly, migration of fibroblasts from patients with pulmonary fibrosis was inhibited in the presence of CXCL10 protein defective in CXCR3 binding. Furthermore, administration of recombinant CXCL10 protein inhibited fibrosis in WT mice, but not in Sdc4-/- mice. Collectively, these data suggest that the direct interaction of syndecan-4 and CXCL10 in the lung interstitial compartment serves to inhibit fibroblast recruitment and subsequent fibrosis. Thus, administration of CXCL10 protein defective in CXCR3 binding may represent a novel therapy for pulmonary fibrosis.

Denitrification and inference of nitrogen sources in the karstic Floridan Aquifer

Aquifer denitrification is among the most poorly constrained fluxes in global and regional nitrogen budgets. The few direct measurements of denitrification in groundwaters provide limited information about its spatial and temporal variability, particularly at the scale of whole aquifers. Uncertainty in estimates of denitrification may also lead to underestimates of its effect on isotopic signatures of inorganic N, and thereby confound the inference of N source from these data. In this study, our objectives are to quantify the magnitude and variability of denitrification in the Upper Floridan Aquifer (UFA) and evaluate its effect on N isotopic signatures at the regional scale. Using dual noble gas tracers (Ne, Ar) to generate physical predictions of N2 gas concentrations for 112 observations from 61 UFA springs, we show that excess (i.e. denitrification-derived) N2 is highly variable in space and inversely correlated with dissolved oxygen (O2). Negative relationships between O2 and δ15N NO3 across a larger dataset of 113 springs, well-constrained isotopic fractionation coefficients, and strong 15N:18O covariation further support inferences of denitrification in this uniquely organic-matter-poor system. Despite relatively low average rates, denitrification accounted for 32 % of estimated aquifer N inputs across all sampled UFA springs. Back-calculations of source δ15N NO3 based on denitrification progression suggest that isotopically-enriched nitrate (NO3-) in many springs of the UFA reflects groundwater denitrification rather than urban- or animal-derived inputs. © Author(s) 2012.