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Although aging and lung injury are linked to the development of idiopathic pulmonary fibrosis (IPF), the underlying pathognomonic processes predisposing to fibrotic lesions remain largely unknown. A deficiency in the ability of type 2 alveolar epithelial cell (AEC2) progenitors to regenerate and repair the epithelia has been proposed as a critical factor. In this issue of the JCI, Liang et al. identify a deficiency in the zinc transporter SLC39A8 (ZIP8) in AEC2s and in the subsequent activation of the sirtuin SIRT1 that predisposes to decreased AEC2 renewal capacity and enhanced lung fibrosis in both IPF and aging lungs. Interestingly, the authors demonstrate the efficacy of modulating dietary zinc levels, suggesting the need for clinical trials to evaluate the therapeutic potential of dietary supplementation and the development of pharmacological modulation of the Zn/ZIP8/SIRT1 axis for treatment.

BackgroundThe anti-inflammatory effect of an α7nAChR agonist, PNU-282987, has previously been explored in the context of inflammatory disease. However, the effects of PNU-282987 on type 2 innate lymphoid cells (ILC2s)-mediated allergic airway inflammation has not yet been established.AimsTo determine the effects of PNU-282987 on the function of ILC2s in the context of IL-33– or Alternaria Alternata (AA)– induced airway inflammation.MethodsPNU-282987 was administered to mice that received recombinant IL-33 or AA intranasal challenges. Lung histological analysis and flow cytometry were performed to determine airway inflammation and the infiltration and activation of ILC2s. The previously published α7nAChR agonist GTS-21 was employed as a comparable reagent. ILC2s were isolated from murine lung tissue and cultured in vitro in the presence of IL-33, IL-2, and IL-7 with/without either PNU-282987 or GTS-21. The expression of the transcription factors GATA3, IKK, and NF-κB were also determined.ResultsPNU-282987 and GTS-21 significantly reduced goblet cell hyperplasia in the airway, eosinophil infiltration, and ILC2s numbers in BALF, following IL-33 or AA challenge. In vitro IL-33 stimulation of isolated lung ILC2s showed a reduction of GATA3 and Ki67 in response to PNU-282987 or GTS-21 treatments. There was a significant reduction in IKK and NF-κB phosphorylation in the PNU-282987–treated group when compared to the GTS-21–treated ILC2s.ConclusionPNU-282987 inhibits ILC2-associated airway inflammation, where its effects were comparable to that of GTS-21.

Isolated cortical vein thrombosis is an uncommon condition and often difficult to diagnose, both clinically and radiologically. We report a case of a 38 years old man who presented with headache of new onset and clinical examination was unremarkable. The unenhanced brain CT did not reveal any abnormality. In view of unrelenting headache and partial seizures, we performed magnetic resonance imaging (with axial T1, T2 and gradient echo sequences, coronal FLAIR, diffusion weighted imaging as well as Gadolinium contrast-enhanced images) and magnetic resonance venography of the brain that revealed an isolated parietal cortical vein thrombosis with the rarely reported 'cord sign'. We report the clinical and radiological findings in our patient with isolated parietal cortical vein thrombosis.

MicroRNAs (miRNAs) are small non-coding RNA molecules that modulate expression of the majority of genes by inhibiting protein translation. Growing literature has identified functional roles for miRNAs across a broad range of biological processes. As such, miRNAs are recognised as potential disease biomarkers and novel targets for therapies. While several miRNA-targeted therapies are currently in clinical trials (e.g. for the treatment of hepatitis C virus infection and cancer), no therapies have targeted miRNAs in respiratory diseases in the clinic. In this mini-review, we review the current knowledge on miRNA expression and function in respiratory diseases, intervention strategies to target miRNA function and considerations specific to respiratory diseases. Altered miRNA expression profiles have been reported in a number of respiratory diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis and idiopathic pulmonary fibrosis. These include alterations in isolated lung tissue, as well as sputum, bronchoalveolar lavage fluids and peripheral blood or serum. The observed alterations in easily accessible body fluids (e.g. serum) have been proposed as new biomarkers that may inform disease diagnosis and patient management. In a subset of studies, miRNA-targeted interventions also improved disease outcomes, indicating functional roles for altered miRNA expression in disease pathogenesis. In fact, direct administration of miRNA-targeting molecules to the lung has yielded promising results in a number of animal models. The ability to directly administer compounds to the lung holds considerable promise and may limit potential off-target effects and side effects caused by the systemic administration required to treat other diseases.

[This corrects the article DOI: 10.1371/journal.ppat.1004549.].

Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

MicroRNAs are post-transcriptional regulators of gene expression that are differentially regulated during development and in inflammatory diseases. A role for miRNAs in allergic asthma is emerging and further investigation is required to determine whether they may serve as potential therapeutic targets. We profiled miRNA expression in murine lungs from an ovalbumin-induced allergic airways disease model, and compared expression to animals receiving dexamethasone treatment and non-allergic controls. Our analysis identified 29 miRNAs that were significantly altered during allergic inflammation. Target prediction analysis revealed novel genes with altered expression in allergic airways disease and suggests synergistic miRNA regulation of target mRNAs. To assess the impacts of one induced miRNA on pathology, we targeted miR-155-5p using a specific antagomir. Antagomir administration successfully reduced miR-155-5p expression with high specificity, but failed to alter the disease phenotype. Interestingly, further investigation revealed that antagomir delivery has variable efficacy across different immune cell types, effectively targeting myeloid cell populations, but exhibiting poor uptake in lymphocytes. Our findings demonstrate that antagomir-based targeting of miRNA function in the lung is highly specific, but highlights cell-specificity as a key limitation to be considered for antagomir-based strategies as therapeutics.

BACKGROUND: Emerging evidence suggests that non-olfactory tissues and cells can express olfactory receptors (ORs), however, the exact function of ectopic OR expression remains unknown. We have previously shown in mouse models that a unique cooperation between interferon-γ (IFN-γ) and lipopolysaccharide (LPS) drives the activation of pulmonary macrophages and leads to the induction of pathogenic responses in the respiratory tract. Further, through gene array studies, we have shown that activation of macrophages by these molecules results in the selective expression of a number of ORs. In this study, we validated the expression of these ORs in mouse airway and pulmonary macrophages in response to IFN-γ and LPS (γ/LPS) stimulation, and further explored the effect of odorant stimulation on macrophage function. METHODOLOGY/PRINCIPAL FINDINGS: OR expression in airway and pulmonary macrophages in response to IFN-γ, LPS or γ/LPS treatments was assessed by microarray and validated by q-PCR. OR expression (e.g. OR622) on macrophages was confirmed by visualization in immunofluoresence assays. Functional responses to odorants were assessed by quantifying inflammatory cytokine and chemokine expression using q-PCR and cell migration was assessed by a modified Boyden chamber migration assay. Our results demonstrate that eight ORs are expressed at basal levels in both airway and pulmonary macrophages, and that γ/LPS stimulation cooperatively increased this expression. Pulmonary macrophages exposed to the combined treatment of γ/LPS+octanal (an odorant) exhibited a 3-fold increase in MCP-1 protein production, compared to cells treated with γ/LPS alone. Supernatants from γ/LPS+octanal exposed macrophages also increased macrophage migration in vitro. CONCLUSIONS/SIGNIFICANCE: Eight different ORs are expressed at basal levels in pulmonary macrophages and expression is upregulated by the synergistic action of γ/LPS. Octanal stimulation further increased MCP-1 production and the motility of macrophages. Our results suggest that ORs may mediate macrophage function by regulating MCP-1 production and cell migration.

Asthma Asthma is a chronic inflammatory disorder of the airways with mixed lymphocytic and myelogenous (e.g., granulocytes/ monocytes) infiltrates (1). Although the inflammatory response is complex, many patients with asthma [...], Allergic asthma is a chronic inflammatory airway disease characterized by dysregulated type 2 immune responses, including degranulating airway eosinophils that induce tissue damage and airway hyperresponsiveness (AHR). The type 2 cytokines interleukin 5 (IL-5) and IL-13 and the eosinophil-specific chemokine CCL11/CCL24/CCL26 axis recruit, activate, and regulate eosinophils in the airways. In this issue of the JCI, Karcz et al. identified a mechanism involving the nucleotide sugar UDP-glucose (UDP-G) and the purinergic receptor [P2Y.sub.14]R in amplifying eosinophil accumulation in the lung. During type 2 inflammation, UDP-G activates [P2Y.sub.14]R on eosinophils, inducing the cells to move and migrate into the lung. Pharmacologically or genetically inhibiting [P2Y.sub.14]R on eosinophils attenuated eosinophil infiltration and AHR. Future experiments, including identifying additional type 2 factors regulating [P2Y.sub.14]R expression on lung eosinophils, are necessary to ascertain the impact of targeting [P2Y.sub.14]R as an alternative or adjunctive therapy to current type 2 biologics for the treatment of asthma.