Background It is well known that liver and lung injury can occur simultaneously during severe inflammation (e.g. multiple organ failure). However, whether these are parallel or interdependent (i.e. liver:lung axis) mechanisms is unclear. Previous studies have shown that chronic ethanol consumption greatly increases mortality in the setting of sepsis-induced acute lung injury (ALI). The potential contribution of subclinical liver disease in driving this effect of Ethanol on the lung remains unknown. Therefore, the purpose of this study was to characterize the impact of chronic Ethanol exposure on concomitant liver and lung injury. Methods Male mice were exposed to ethanol-containing Lieber-DeCarli diet or pair-fed control diet for 6 weeks. Some animals were administered lipopolysaccharide (LPS) 4 or 24 hours prior to sacrifice to mimic sepsis-induced ALI. Some animals received the TNFα blocking drug, etanercept, for the duration of alcohol exposure. The expression of cytokine mRNA in lung and liver tissue was determined by qPCR. Cytokine levels in the bronchoalveolar lavage fluid (BALF) and plasma were determined by Luminex assay. Results As expected, the combination of Ethanol and LPS caused liver injury, as indicated by significantly increased levels of the transaminases ALT/AST in the plasma and by changes in liver histology. In the lung, Ethanol preexposure enhanced pulmonary inflammation and alveolar hemorrhage caused by LPS. These changes corresponded with unique alterations in the expression of pro-inflammatory cytokines in the liver (i.e TNFα) and lung (i.e. MIP-2, KC). Systemic depletion of TNFα (etanercept) blunted injury and the increase in MIP-2 and KC caused by the combination of ethanol and LPS in the lung. Conclusions Chronic Ethanol preexposure enhanced both liver and lung injury caused by LPS. Enhanced organ injury corresponded with unique changes in the pro-inflammatory cytokine expression profiles in the liver and the lung.

Summary Plants adapt to environmental changes by regulating transcription and chromatin organization. The histone H2A variant H2A.Z and the SWI2/SNF2 ATPase BRAHMA (BRM) have overlapping roles in positively and negatively regulating environmentally responsive genes in Arabidopsis, but the extent of this overlap was uncharacterized. Both factors have been associated with various changes in nucleosome positioning and stability in different contexts, but their specific roles in transcriptional regulation and chromatin organization need further characterization. We show that H2A.Z and BRM co‐localize at thousands of sites, where they interact both cooperatively and antagonistically in transcriptional repression and activation of genes involved in development and responses to environmental stimuli. We identified eight classes of genes that show distinct relationships between H2A.Z and BRM with respect to their roles in transcription. These include activating and silencing transcription both redundantly and antagonistically. We found that H2A.Z contributes to a range of different nucleosome properties, while BRM stabilizes nucleosomes where it binds and destabilizes or repositions flanking nucleosomes. We also found that, at many genes regulated by both BRM and H2A.Z, both factors overlap with binding sites of the light‐regulated transcription factor FAR1‐Related Sequence 9 (FRS9) and that a subset of these FRS9 binding sites are dependent on H2A.Z and BRM for accessibility. Collectively, we comprehensively characterized the antagonistic and cooperative contributions of H2A.Z and BRM to transcriptional regulation, and illuminated several interrelated roles in chromatin organization. The variability observed in their individual functions implies that both BRM and H2A.Z have more context‐dependent roles than previously assumed.

Long-term success in lung transplantation is limited by obliterative bronchiolits (OB), while the mechanism for this disease is not well-understood. Chemokine SDF-1 and its receptor CXCR4 have been reported to be involved in several fibrogenic processes by recruiting inflammatory and fibroblast progenitor cells into injured tissues. We hypothesized that SDF-1/CXCR4 axis also plays a role in the pathogenesis of OB. Using the mouse heterotopic allogeneic airway transplant model, we transplanted mouse tracheas from Balb/C donors into C57BL/6 recipients. At day 10 after transplant, we found high expression of SDF-1 in cells in sub-epithelial layers of the allograft. Approximately 26% of cells infiltrating the allograft were CD45+CXCR4+ as was determined by flow cytometry analysis. Treatment of the recipients with a CXCR4 antagonist, TN 14003, decreased cell infiltration into the grafts at day 10 post implantation. At day 42 a significant reduction of the luminal occlusion was found in the TN14003 treated animals compared to controls (57.40% versus 98.21%, p<0.01). To demonstrate the relevance of SDF-1/CXCR4 axis in OB, sections of lung tissue obtained from lung transplanted patients with OB, were examined for SDF-1 and CXCR4 expression. We found higher number of CXCR4 and SDF-1 positive cells in samples from patients with OB compared with normal lungs. These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new intervention tools for the treatment of OB.

Plants adapt to changes in their environment by regulating transcription and chromatin organization. The histone H2A variant H2A.Z and the SWI2/SNF2 ATPase BRAHMA have overlapping roles in positively and negatively regulating environmentally responsive genes in Arabidopsis, but the extent of this overlap was uncharacterized. Both have been associated with various changes in nucleosome positioning and stability in different contexts, but their specific roles in transcriptional regulation and chromatin organization need further characterization. We show that H2A.Z and BRM act both cooperatively and antagonistically to contribute directly to transcriptional repression and activation of genes involved in development and response to environmental stimuli. We identified 8 classes of genes that show distinct relationships between H2A.Z and BRM and their roles in transcription. We found that H2A.Z contributes to a range of different nucleosome properties, while BRM stabilizes nucleosomes where it binds and destabilizes and/or repositions flanking nucleosomes. H2A.Z and BRM contribute to +1 nucleosome destabilization, especially where they coordinately regulate transcription. We also found that at genes regulated by both BRM and H2A.Z, both factors overlap with the binding sites of light-regulated transcription factors PIF4, PIF5, and FRS9, and that some of the FRS9 binding sites are dependent on H2A.Z and BRM for accessibility. Collectively, we comprehensively characterized the antagonistic and cooperative contributions of H2A.Z and BRM to transcriptional regulation, and illuminated their interrelated roles in chromatin organization. The variability observed in their individual functions implies that both BRM and H2A.Z have more context-specific roles within diverse chromatin environments than previously assumed.

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