Vasoactive Intestinal Peptide Receptor, CRTH2, Antagonist Treatment Improves Eosinophil and Mast Cell-Mediated Esophageal Remodeling and Motility Dysfunction in Eosinophilic Esophagitis.

BACKGROUND AND AIMS: Ultrasonography has shown that eosinophils accumulate in each segment of the esophageal mucosa in human EoE, ultimately promoting esophageal motility dysfunction; however, no mechanistic evidence explains how or why this accumulation occurs. METHODS: Quantitative PCR, ELISA, flow cytometry, immunostaining, and immunofluorescence analyses were performed using antibodies specific to the related antigens and receptors. RESULTS: In deep esophageal biopsies of EoE patients, eosinophils and mast cells accumulate adjacent to nerve cell-derived VIP in each esophageal segment. qRT-PCR analysis revealed five- to sixfold increases in expression levels of VIP, CRTH2, and VAPC2 receptors and proteins in human blood- and tissue-accumulated eosinophils and mast cells. We also observed a significant correlation between mRNA CRTH2 levels and eosinophil- and nerve cell-derived VIPs in human EoE (p < 0.05). We provide evidence that eosinophil and mast cell deficiency following CRTH2 antagonist treatment improves motility dysfunction in a chronic DOX-inducible CC10-IL-13 murine model of experimental EoE. CONCLUSIONS: CRTH2 antagonist treatment is a novel therapeutic strategy for inflammatory cell-induced esophageal motility dysfunction in IL-13-induced chronic experimental EoE.

IMPETUS Stroke: Assessment of hospital infrastructure and workflow for implementation of uniform stroke care pathway in India.

BACKGROUND: India accounts for 13.3% of global disability-adjusted life years (DALYs) lost due to stroke with a relatively younger age of onset compared to the Western population. In India's public healthcare system, many stroke patients seek care at tertiary-level government-funded medical colleges where an optimal level of stroke care is expected. However, there are no studies from India that have assessed the quality of stroke care, including infrastructure, imaging facilities, or the availability of stroke care units in medical colleges. AIM: This study aimed to understand the existing protocols and management of acute stroke care across 22 medical colleges in India, as part of the baseline assessment of the ongoing IMPETUS stroke study. METHODS: A semi-structured quantitative pre-tested questionnaire, developed based on review of literature and expert discussion, was mailed to 22 participating sites of the IMPETUS stroke study. The questionnaire assessed comprehensively all components of stroke care, including human resources, emergency system, in-hospital care, and secondary prevention. A descriptive analysis of their status was undertaken. RESULTS: In the emergency services, limited stroke helpline numbers, 3/22 (14%); prenotification system, 5/22 (23%); and stroke-trained physicians were available, 6/22 (27%). One-third of hospitals did not have on-call neurologists. Although non-contrast computed tomography (NCCT) was always available, 39% of hospitals were not doing computed tomography (CT) angiography and 13/22 (59%) were not doing magnetic resonance imaging (MRI) after routine working hours. Intravenous thrombolysis was being done in 20/22 (91%) hospitals, but 36% of hospitals did not provide it free of cost. Endovascular therapy was available only in 6/22 (27%) hospitals. The study highlighted the scarcity of multidisciplinary stroke teams, 8/22 (36%), and stroke units, 7/22 (32%). Lifesaving surgeries like hematoma evacuation, 11/22 (50%), and decompressive craniectomy, 9/22 (41%), were performed in limited numbers. The availability of occupational therapists, speech therapists, and cognitive rehabilitation was minimal. CONCLUSION: This study highlighted the current status of acute stroke management in publicly funded tertiary care hospitals. Lack of prenotification, limited number of stroke-trained physicians and neurosurgeons, relatively lesser provision of free thrombolytic agents, limited stroke units, and lack of rehabilitation services are areas needing urgent attention by policymakers and creation of sustainable education models for uniform stroke care by medical professionals across the country.

Study Protocol: IMPETUS: Implementing a Uniform Stroke Care Pathway in Medical Colleges of India: IMPETUS Stroke.

Introduction: In India, a national program for stroke (national programme for the control of cardiovascular diseases, diabetes, cancer, and stroke) and stroke management guidelines exist. Its successful implementation would need an organized system of stroke care in practice. However, many challenges exist including lack of awareness, prehospital notification systems, stroke ready hospitals, infrastructural weaknesses, and rehabilitation. We present here a protocol to investigate the feasibility and fidelity of implementing a uniform stroke care pathway in medical colleges of India. Methods and Analysis: This is a multicentric, prospective, multiphase, mixed-method, quasi-experimental implementation study intended to examine the changes in a select set of stroke care-related indicators over time within the sites exposed to the same implementation strategy. We shall conduct process evaluation of the implementation process as well as evaluate the effect of the implementation strategy using the interrupted time series design. During implementation phase, education and training about standard stroke care pathway will be provided to all stakeholders of implementing sites. Patient-level outcomes in the form of modified Rankin Scale score will be collected for all consecutive patients throughout the study. Process evaluation outcomes will be collected and reported in the form of various stroke care indicators. We will report level and trend changes in various indicators during the three study phases. Discussion: Acute stroke requires timely detection, management, and secondary prevention. Implementation of the uniform stroke care pathway is a unique opportunity to promote the requirements of homogenous stroke care in medical colleges of India.

Augmenter of liver regeneration: Mitochondrial function and steatohepatitis.

Augmenter of liver regeneration (ALR), a ubiquitous fundamental life protein, is expressed more abundantly in the liver than other organs. Expression of ALR is highest in hepatocytes, which also constitutively secrete it. ALR gene transcription is regulated by NRF2, FOXA2, SP1, HNF4α, EGR-1 and AP1/AP4. ALR's FAD-linked sulfhydryl oxidase activity is essential for protein folding in the mitochondrial intermembrane space. ALR's functions also include cytochrome c reductase and protein Fe/S maturation activities. ALR depletion from hepatocytes leads to increased oxidative stress, impaired ATP synthesis and apoptosis/necrosis. Loss of ALR's functions due to homozygous mutation causes severe mitochondrial defects and congenital progressive multiorgan failure, suggesting that individuals with one functional ALR allele might be susceptible to disorders involving compromised mitochondrial function. Genetic ablation of ALR from hepatocytes induces structural and functional mitochondrial abnormalities, dysregulation of lipid homeostasis and development of steatohepatitis. High-fat diet-fed ALR-deficient mice develop non-alcoholic steatohepatitis (NASH) and fibrosis, while hepatic and serum levels of ALR are lower than normal in human NASH and NASH-cirrhosis. Thus, ALR deficiency may be a critical predisposing factor in the pathogenesis and progression of NASH.

Macrophages-induced IL-18-mediated eosinophilia promotes characteristics of pancreatic malignancy.

Reports indicate that accumulated macrophages in the pancreas are responsible for promoting the pathogenesis of chronic pancreatitis (CP). Recently, macrophage-secreted cytokines have been implicated in promoting pancreatic acinar-to-ductal metaplasia (ADM). This study aims to establish the role of accumulated macrophage-activated NLRP3-IL-18-eosinophil mechanistic pathway in promoting several characteristics of pancreatic malignancy in CP. We report that in a murine model of pancreatic cancer (PC), accumulated macrophages are the source of NLRP3-regulated IL-18, which promotes eosinophilic inflammation-mediated accumulation to periductal mucin and collagen, including the formation of ADM, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasm. Most importantly, we show improved malignant characteristics with reduced levels of oncogenes in an anti-IL-18 neutralized and IL-18 gene deficient murine model of CP. Last, human biopsies validated that NLRP3-IL-18-induced eosinophils accumulate near the ducts, showing PanINs formation in PC. Taken together, we present the evidence on the role of IL-18-induced eosinophilia in the development of PC phenotype like ADM, PanINs, and ductal cell differentiation in inflammation-induced CP.

Cognitive impairment in type 2 diabetes and its impact on daily living and self-care: A case - Control study in Kanpur, North India.

BACKGROUND AND AIM: There have been few studies from South Asia which have shown increased prevalence of cognitive impairment (CI) in diabetes. CI may further hamper self-care and independent living. The present study was designed to evaluate the impairment in cognition and self-care among patients with type 2 diabetes. MATERIALS AND METHODS: We assessed cognitive function in 54 type 2 diabetes participants and compared them with 54 healthy controls, using Addenbrooke's Cognitive Examination-III (ACE-III) test. Assessment of self-care was done by using Katz index of independence in activities of daily living and revised Summary of Diabetes Self-Care Activities (SDSCA) measures. RESULTS: The mean age and HbA1c of cases was 64.5 ± 5.3 years and 8.8 ± 2.5%, respectively. Cognitive impairment was more prevalent among type 2 diabetes participants (Odds ratio 31.3, CI: 10-100, P < 0.0001) with mean Addenbrooke's score of 74.9 ± 11.2 compared to 86.9 ± 5.3 in controls (t-statistic = 7.09, 95% CI: 8.6 to 15.3, P < 0.0001). The adjusted Odds ratio for CI was 9.46 after adjustment for hypertension. All the sub-domains of cognition were affected. The burden of CI was more among females and in those with poor glycemic control (HbA1C > 7.5%) when compared to controls. The diabetic participants with CI had poor SDSCA scores compared to those with no CI. CONCLUSION: Diabetes may cause CI and is related to poor self-care. Considering a high prevalence of CI in diabetes, cognitive assessment should be a part of overall evaluation. ACE-III is a sensitive and convenient tool for this purpose.

Tacrolimus (FK506) treatment protects allergen-, IL-5- and IL-13-induced mucosal eosinophilia.

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F+ eosinophils in Aspergillus-challenged asthma and EoE, CD2-IL-5 induced global eosinophilia, and DOX regulated IL-13-induced asthma. We used flow cytometry and anti-major basic protein (MBP) immunostaining to examine eosinophils in the spleen, bone marrow, BALF, lung, oesophagus and intestine. Additionally, we also performed ELISA and Western blot analyses to show that tacrolimus treatment also reduces the levels of eosinophil-specific cytokines IL-4, IL-5, IL-13 and TGF-ß, eosinophil-specific chemokines Eotaxin-1 and Eotaxin-2, and progenitors of target RCAN1 mRNA and protein levels. Additionally, the current investigations also show that the TGF-ß-mediated oesophageal and lung fibrosis is also reduced in Aspergillus-challenged, CD2-IL-5 transgenic and DOX-responsive IL-13 mice. Mechanistically, we show that tacrolimus in vitro treatment inhibited bone marrow-derived eosinophil proliferation and viability by promoting eosinophil apoptosis that may be associated with downregulation of RCAN1. Taken together, we provide in vivo and in vitro evidence that tacrolimus ameliorates eosinophil levels and associated pathogenesis in allergen-, IL-5- and IL-13-induced EoE, EG and asthma pathogenesis. Considering tacrolimus side-effects and reactivity to several other drugs, we propose the topical use of tacrolimus for paediatric and low-dose oral for adult patients as a novel therapeutic strategy for the clinical trial to reduce mucosal eosinophilia first in steroid-refractory or elemental diet non-responsive adult EoE, EG and asthma patients.

Antibacterial and cellular response of piezoelectric Na0.5K0.5NbO3modified 1393 bioactive glass.

In the present study, the combined effect of addition of varying concentrations (10-30 vol%) of biocompatible piezoelectric Na0.5K0.5NbO3 (NKN) as well as electrostatic and dynamic pulsed electrical treatment on antibacterial and cellular response of 1393 bioactive glass (1393 BG) has been examined. The phase analyses of the sintered (at 800 °C for 30 min) samples revealed the formation of 1393 BG - NKN composites without any appearance of secondary phases. The addition of 10-30 vol% NKN significantly improved the mechanical behaviour of 1393 BG like, hardness (1.7 to 2 times), fracture toughness (1.3 to 2.6 times), compressive (2.3 to 8 times) and flexural strengths (2 to 3.5 times) than monolithic 1393 BG. The piezoelectric NKN is observed to induce the antibacterial activity in 1393 BG - (10- 30 vol%) NKN composites, while Staphylococcus aureus (S. aureus, gram positive) and Escherichia coli (E. coli, gram negative) bacterial cells were exposed to unpolarized and polarized (20 kV, 500°C for 30 min) sample surfaces. The antibacterial response was examined using disc diffusion, nitro blue tetrazolium (NBT) and MTT assays. The statistical analyses revealed the significant reduction in the viability of bacterial cells on polarized 1393 BG - (10- 30 vol%) NKN composite samples. In addition, the combined effect of electrostatic and dynamic pulsed electrical stimulation (1 V/cm, 500 µs pulses) on the cellular response of 1393 BG and 1393 BG - 30 vol% NKN composites has been analysed with MG-63 osteoblast-like cells. The cell proliferation was observed to increase significantly for the dynamic pulsed electric field treated negatively charged surfaces.

Eosinophilic pancreatitis: a rare or unexplored disease entity?

Several case reports show accumulation of eosinophils in pancreatitis patients and term the disease as "eosinophilic pancreatitis (EP)". EP usually presents with a pancreatic tumour and abdominal pain in obstructive jaundice, which is generally not diagnosed until the patient undergoes pancreatic resection. Histologically, EP reveals distinct patterns like diffused, periductal, acinar, and septal inflammatory infiltrates with eosinophils, eosinophilic phlebitis, and localised extreme eosinophilic infiltrates related with pseudocyst formation. EP patients also have elevated serum IgE levels with high eosinophil counts in the pancreas as well as in other organs such as the gastrointestinal tract, which is termed as eosinophilic gastroenteritis. Due to the lack of knowledge based on just a few case reports, it is considered that eosinophilic infiltration is quite rare in the pancreas; therefore, the significance of eosinophils in pancreatitis is not yet established. This review assesses the current understanding of eosinophilic pancreatitis and the important role of eosinophils in promoting pancreatic fibrosis including malignancy.

Lipopolysaccharide Reverses Hepatic Stellate Cell Activation Through Modulation of cMyb, Small Mothers Against Decapentaplegic, and CCAAT/Enhancer-Binding Protein C/EBP Transcription Factors.

BACKGROUND AND AIMS: During liver injury, quiescent hepatic stellate cells (qHSCs) transdifferentiate into proliferative and fibrogenic activated myofibroblastic phenotype (activated hepatic stellate cell; aHSCs) expressing smooth muscle α-actin (αSMA) and platelet-derived growth factor beta receptor (PDGFßR). Their interactions with gut-derived bacterial lipopolysaccharide (LPS) are implicated in hepatic fibrogenesis. However, LPS can also attenuate fibrogenic characteristics of aHSCs. APPROACH AND RESULTS: We examined molecular mechanisms of antifibrogenic effects of LPS on aHSCs in vitro and in vivo. Culture-activated rat HSCs were exposed to 0-100 ng/mL of LPS or its active component, diphosphoryl-lipid A (DPLA), and parameters of fibrosis and inflammatory cytokines/chemokines were determined by qRT-PCR, western, and immunohistochemical analyses. In vivo, HSCs were activated by repeated CCl4 administration to rats every 3 days for 3 or 8 weeks, then challenged with LPS (5 mg/kg; IP). HSCs were isolated 24 hours later, and fibrogenic/inflammatory parameters were analyzed. LPS induced phenotypic changes in aHSCs (rounding, size reduction) and loss of proliferation. LPS down-regulated expression of αSMA, PDGFßR, transforming growth factor beta receptor 1 (TGFßR1), collagen 1α1 (Col1α1), and fibronectin while up-regulating tumor necrosis factor alpha, interleukin-6, and C-X-C motif chemokine ligand 1 expression. LPS did not increase peroxisome proliferation-activated receptor gamma expression or lipid accumulation typical of qHSCs. DPLA elicited the same effects as LPS on aHSCs, indicating specificity, and monophosphoryl lipid A down-regulated fibrogenic markers, but elicited very weak inflammatory response. LPS down-regulated the expression of cMyb, a transcription factor for αSMA, and up-regulated small mother against decapentaplegic (SMAD)7 and CCAAT/enhancer-binding protein (C/EBP)δ, the transcriptional inhibitors of Col1α1 expression. In vivo LPS treatment of aHSCs inhibited their proliferation, down-regulated PDGFßR, αSMA, TGFßR1, Col1α1, and cMyb expression, and increased expression of SMAD7, C/EBPα, and C/EBPδ. CONCLUSIONS: In conclusion, LPS induces a unique phenotype in aHSCs associated with down-regulation of key fibrogenic mechanisms and thus may have an important role in limiting fibrosis.

Hepatic Deficiency of Augmenter of Liver Regeneration Predisposes to Nonalcoholic Steatohepatitis and Fibrosis.

BACKGROUND AND AIMS: The augmenter of liver regeneration (ALR) protein is critical for lipid homeostasis and mitochondrial function. We investigated high-fat/high-carbohydrate (HF/HC) diet-induced nonalcoholic fatty liver disease (NAFLD) in wild-type (WT), hepatocyte-specific ALR-knockout (ALR-H-KO), and ALR-heterozygous (ALR-H-HET) mice. ALR was measured in serum of human nonalcoholic steatohepatitis (NASH) and NASH-induced cirrhosis (serum and liver). APPROACH AND RESULTS: HF/HC feeding decreased ALR expression in all groups of mice. The otherwise normal ALR-H-HET mice gained more weight and steatosis than WT mice when challenged metabolically with the HF/HC diet; ALR-H-KO mice gained the least weight and had the least steatosis. These findings were consistent with correspondingly increased triglycerides and cholesterol and altered expression of carnitine palmitoyltransferase 1a, sterol regulatory element-binding protein, acetyl coenzyme A carboxylase, and fatty acid synthase. All HF/HC-fed mice developed insulin resistance, the magnitude being lower in ALR-H-KO mice. HF/HC-fed ALR-H-HET mice were more resistant to glucose challenge than WT or ALR-H-KO mice. The frequency of tumor necrosis factor alpha-producing, interleukin 6 (IL6)-producing, and IL17-producing cells was greater in ALR-H-KO than ALR-H-HET and lowest in WT mice. HF/HC feeding did not increase their number in ALR-H-KO mice, and the increase in ALR-H-HET was greater than that in WT mice except for IL17 cells. Cluster of differentiation 25-positive (CD25+ ) forkhead box P3-positive CD4+ regulatory T-cell frequency was lower in ALR-H-HET than WT mice and further reduced in ALR-H-KO mice; HF/HC reduced regulatory T-cell frequency only in WT mice. HF/HC-fed ALR-H-HET, but not WT, mice developed fibrosis; and ALR-H-KO mice progressed to cirrhosis. White adipose tissue of HF/HC-fed ALR-deficient mice developed strong inflammation, indicating bidirectional interactions with the liver. Hepatic and serum ALR levels were significantly reduced in patients with NASH-cirrhosis. Serum ALR was also significantly lower in patients with NASH. CONCLUSIONS: Hepatic ALR deficiency may be a critical predisposing factor for aggressive NAFLD progression.

Electro-mechanical and Polarization-Induced Antibacterial Response of 45S5 Bioglass-Sodium Potassium Niobate Piezoelectric Ceramic Composites.

Besides the excellent osteoconductivity and biocompatibility of 45S5 bioglass (BG), poor mechanical and electrical properties as well as susceptibility toward bacterial adhesion limit its widespread clinical applications. In this context, the present study investigates the effect of addition of piezoelectric sodium potassium niobate (Na0.5K0.5NbO3; NKN) on mechanical, dielectric, and antibacterial response of BG. BG-xNKN (x = 0, 10, 20, and 30 vol%) composites were synthesized at 800 °C for 30 min. The phase analyses using spectral techniques revealed the formation of the composite without any reaction between BG and piezoelectric ceramic NKN. The dielectric and electrical measurements were performed over a wide range of temperature (30-500 °C) and frequency (1 Hz-1 MHz) which suggests that space charge and dipolar polarizations are the dominant polarization mechanisms. The complex impedance analyses suggest that the average activation energies for grain and grain boundary resistances for BG-xNKN (x = 10, 20, and 30 vol%) composites are 0.59, 0.87, 0.94 and 0.76, 0.93, 1.06 eV, respectively. The issue of bacterial infection has been addressed by electrical polarization of the developed composite samples, at 20 kV for 30 min. Statistical analyses reveal that the viability of Gram-positive (S. aureus) and Gram-negative (E. coli) bacterial cells has been reduced significantly on positively and negatively charged BG-NKN composite samples, respectively. The qualitative analyses using the Kirby-Bauer test supports the above findings. Nitro blue tetrazolium and lipid peroxide assays were performed to understand the mechanism of such antibacterial response, which suggested that the combined effect of NKN addition and polarization significantly enhances the superoxide production, which kills the bacterial cells. Overall, incorporation of NKN in BG enhances the mechanical, electrical, and dielectric properties as well as improves the antibacterial response of polarized BG-xNKN composites.

Multifunctional Response of Piezoelectric Sodium Potassium Niobate (NKN)-Toughened Hydroxyapatite-Based Biocomposites.

In this study, hydroxyapatite (HA)-sodium potassium niobate (NKN) composites with varying concentrations of NKN (10, 20, and 30 wt %) were optimally developed at 1075 °C for 2 h. Detailed microstructural analyses have been performed by means of scanning and transmission electron microscopy. The maximum fracture toughness, hardness, and compressive and flexural strengths were obtained to be ∼209, ∼93, ∼112, and ∼88%, respectively, for the HA-30 wt % NKN composite compared to monolithic HA. The antibacterial tests revealed the significant reduction in bacterial viability on poled (@ 20 kV for 30 min at 500 °C) HA-NKN composite samples while cultured with Staphylococcus aureus and Escherichia coli bacteria. The cytocompatibility tests revealed the significantly enhanced MG63 cell proliferation for electrical stimulation-treated negatively charged HA and H30N composite samples.

Photometric Depth Super-Resolution.

This study explores the use of photometric techniques (shape-from-shading and uncalibrated photometric stereo) for upsampling the low-resolution depth map from an RGB-D sensor to the higher resolution of the companion RGB image. A single-shot variational approach is first put forward, which is effective as long as the target's reflectance is piecewise-constant. It is then shown that this dependency upon a specific reflectance model can be relaxed by focusing on a specific class of objects (e.g., faces), and delegate reflectance estimation to a deep neural network. A multi-shot strategy based on randomly varying lighting conditions is eventually discussed. It requires no training or prior on the reflectance, yet this comes at the price of a dedicated acquisition setup. Both quantitative and qualitative evaluations illustrate the effectiveness of the proposed methods on synthetic and real-world scenarios.

Simultaneous lateral column shortening along with differential distraction by Joshi's external stabilization system for rigid neglected clubfoot correction.

Correction of rigid clubfoot in an older child by gradual differential distraction using the Ilizarov's device or Joshi's external stabilization system (JESS) is a time-consuming procedure. We simultaneously combined the lateral column shortening by cuboid wedge resection along with the differential distraction by application of JESS fixator for the treatment of severe, rigid, neglected, or relapsed congenital talipes equinovarus (CTEV) foot deformity in 30 feet in 18 children with mean age of 5.3 years and mean follow-up of 27.6 months. The mean pretreatment Pirani score was 5.3 which improved to mean Pirani score after treatment of 1.4. Excellent results were obtained in 22 (71.33%) feet, good results in four (13.33%) feet, and poor results in four (13.33%) feet. The average period for distraction in our series was 6.3 weeks, and total average period of fixator in place was 11.2 weeks. To conclude, lateral column shortening with JESS application simultaneously gives early good to excellent short-term results, and the combination of techniques permits rapid correction of deformity, and thus reducing the time for which the fixator is in place and hence has better acceptance by the patient.

Attenuation of Allergen-, IL-13-, and TGF-α-induced Lung Fibrosis after the Treatment of rIL-15 in Mice.

Endogenous IL-15 deficiency promotes lung fibrosis; therefore, we examined the effect of induced IL-15 in restricting the progression of lung fibrosis. Our objective in this work was to establish a novel therapeutic molecule for pulmonary fibrosis. Western blot, qPCR, and ELISA were performed on the lung tissues of IL-15-deficient mice, and recombinant IL-15 (rIL-15)-treated CC10-IL-13 and CC10-TGF-α mice, and allergen-challenged CC10-IL-15 mice were examined to establish the antifibrotic effect of IL-15 in lung fibrosis. We show that endogenous IL-15 deficiency induces baseline profibrotic cytokine and collagen accumulation in the lung, and pharmacological delivery of rIL-15 downregulates Aspergillus antigen-induced lung collagen, the profibrotic cytokines IL-13 and TGF-ß1, and α-SMA+ and FSP1+ cells in mice. To confirm that overexpression of IL-15 diminishes pulmonary fibrosis, we generated CC10-rtTA-tetO7-IL-15 transgenic mice and challenged them with Aspergillus antigen. Aspergillus antigen-challenged, doxycycline (DOX)-treated CC10-IL-15 transgenic mice exhibited decreased collagen accumulation, profibrotic cytokine (IL-13 and TGF-ß1) expression, and α-SMA+ and FSP1+ cells compared with IL-15-overexpressing mice not treated with DOX. Additionally, to establish that the antifibrotic effect of IL-15 is not limited to allergen-induced fibrosis, we showed that rIL-15 or IL-15 agonist treatment restricted pulmonary fibrosis even in CC10-IL-13 and CC10-TGF-α mice. Mechanistically, we show that T-helper cell type 17 suppressor IL-15-responsive RORγ+ T regulatory cells are induced in DOX-treated, allergen-challenged IL-15-overexpressing mice, which may be a novel pathway for restricting progression of pulmonary fibrosis. Taken together, our data establishes antifibrotic activity of IL-15 that might be a novel therapeutic molecule to combat the development of pulmonary fibrosis.

Intestinal overexpression of IL-18 promotes eosinophils-mediated allergic disorders.

Baseline eosinophils reside in the gastrointestinal tract; however, in several allergic disorders, excessive eosinophils accumulate in the blood as well in the tissues. Recently, we showed in vitro that interleukin (IL)-18 matures and transforms IL-5-generated eosinophils into the pathogenic eosinophils that are detected in human allergic diseases. To examine the role of local induction of IL-18 in promoting eosinophil-associated intestinal disorders, we generated enterocyte IL-18-overexpressing mice using the rat intestinal fatty acid-binding promoter (Fabpi) and analysed tissue IL-18 overexpression and eosinophilia by performing real-time polymerase chain reaction, Enzyme-Linked Immunosorbent Assay and anti-major basic protein immunostaining. Herein we show that Fabpi-IL-18 mice display highly induced IL-18 mRNA and protein in the jejunum. IL-18 overexpression in enterocytes promotes marked increases of eosinophils in the blood and jejunum. Our analysis shows IL-18 overexpression in the jejunum induces a specific population of CD101+  CD274+ tissue eosinophils. Additionally, we observed comparable tissue eosinophilia in IL-13-deficient-Fabpi-IL-18 mice, and reduced numbers of tissue eosinophils in eotaxin-deficient-Fabpi-IL-18 and IL-5-deficient-Fabpi-IL-18 mice compared with Fabpi-IL-18 transgenic mice. Notably, jejunum eosinophilia in IL-5-deficient-Fabpi-IL-18 mice is significantly induced compared with wild-type mice, which indicates the direct role of induced IL-18 in the tissue accumulation of eosinophils and mast cells. Furthermore, we also found that overexpression of IL-18 in the intestine promotes eosinophil-associated peanut-induced allergic responses in mice. Taken together, we provide direct in vivo evidence that induced expression of IL-18 in the enterocytes promotes eotaxin-1, IL-5 and IL-13 independent intestinal eosinophilia, which signifies the clinical relevance of induced IL-18 in eosinophil-associated gastrointestinal disorders (EGIDs) to food allergens.