Publications by authors named "Gabriele Grunig"

41 Publications

An Emotional Molecular Pathway in Pulmonary Hypertension-Alternative Complement System.

Am J Respir Crit Care Med 2020 01;201(2):138-140

Department of MedicineNew York University School of MedicineNew York, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201909-1790EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961743PMC
January 2020

Variability of blood eosinophils in patients in a clinic for severe asthma.

Clin Exp Allergy 2019 02 14;49(2):163-170. Epub 2019 Jan 14.

Department of Medicine, New York University School of Medicine, New York, New York.

Background: Blood eosinophils are used to determine eligibility for agents targeting IL-5 in patients with uncontrolled asthma. However, little is known about the variability of blood eosinophil measures in these patients before treatment initiation.

Objective: To characterize variability and patterns of variability of blood eosinophil levels in a real-world clinic for severe asthmatics.

Methods: Retrospective review of blood eosinophils measured over a 5-year period in patients enrolled in an urban clinic. Repeated measures of blood eosinophil levels in individuals were evaluated, and cluster analysis was performed to characterize patients by eosinophil patterns. Clinical characteristics associated with eosinophil levels and patterns of variability were analysed.

Results: Patients treated in the Bellevue Hospital Asthma Clinic within a 3-month period were identified (n = 219). Blood eosinophil measures were obtained over the previous 5 years. Only 6% (n = 13) of patients had levels that were consistently above 300 cells/μL. Nearly 50% (n = 104) had eosinophil levels that traversed the threshold of 300 cells/μL. In contrast, 102 (46%) had levels that never reached the threshold of 300 cells/μL. Cluster analyses revealed three clusters with differing patterns of levels and variability. There was a suggestion of decreased clinical control and increased atopy in the cluster with the greatest variability in blood eosinophil measures.

Conclusion: In an urban clinic for patients referred for uncontrolled asthma, blood measures of eosinophils were variable and showed differing patterns of variability. These data reinforce the need to perform repeated eosinophil blood measures for appropriate designation for therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cea.13310DOI Listing
February 2019

Pathobiology, pathology and genetics of pulmonary hypertension: Update from the Cologne Consensus Conference 2018.

Int J Cardiol 2018 Dec 20;272S:4-10. Epub 2018 Sep 20.

Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.

The European guidelines, which focus on clinical aspects of pulmonary hypertension (PH), provide only minimal information about the pathophysiological concepts of PH. Here, we review this topic in greater detail, focusing on specific aspects in the pathobiology, pathology and genetics, which include mechanisms of vascular inflammation, the role of transcription factors, ion channels/ion channel diseases, hypoxic pulmonary vasoconstriction, genetics/epigenetics, metabolic dysfunction, and the potential future role of histopathology of PH in the modern era of PH therapy. In addition to new insights in the pathobiology of this disease, this working group of the Cologne Consensus Conference also highlights novel concepts and potential new therapeutic targets to further improve the treatment options in PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2018.09.070DOI Listing
December 2018

An RNA Sensor Protects against Pulmonary Hypertension.

Am J Respir Crit Care Med 2019 01;199(2):138-140

2 Department of Medicine New York University Langone Medical Center New York, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201807-1363EDDOI Listing
January 2019

Circulating MicroRNA Markers for Pulmonary Hypertension in Supervised Exercise Intervention and Nightly Oxygen Intervention.

Front Physiol 2018 25;9:955. Epub 2018 Jul 25.

Mirna Analytics LLC, New York, NY, United States.

Therapeutic exercise training has been shown to significantly improve pulmonary hypertension (PH), including 6-min walking distance and right heart function. Supplemental nightly oxygen also has therapeutic effects. A biomarker tool that could query critical gene networks would aid in understanding the molecular effects of the interventions. Paired bio-banked serum ( = 31) or plasma ( = 21) samples from the exercise or oxygen intervention studies, respectively, and bio-banked plasma samples ( = 20) from high altitude induced PH in cattle were tested. MicroRNAs (miRNAs) markers were chosen for study because they regulate gene expression, control the function of specific gene networks, and are conserved across species. miRNAs that control muscle (miR-22-3p, miR-21-5p) or erythrocyte function (miR-451a) were chosen based on pilot experiments. Plasma samples from cattle that developed PH in high altitude had significantly higher miR-22-3p/(relative to) miR-451a values when compared to control cattle tolerant to high altitude. Measurements of miR-22-3p/miR-451a values in serum from patients receiving exercise training showed that the values were significantly decreased in 74.2% of the samples following intervention and significantly increased in the remainder (25.8%). In samples obtained after exercise intervention, a higher composite miRNA value, made of miR-22-3p and miR-21-5p/miR-451a and spike RNA, was significantly decreased in 65% of the samples and significantly increased in 35% of the samples. In the study of nightly oxygen intervention, when comparing placebo and oxygen, half of the samples showed a significant down-ward change and the other half a significant up-ward change measuring either of the miRNA markers. Samples that had a downward change in the miRNA marker following either intervention originated from patients who had a significantly higher 6-min-walking-distance at baseline (mean difference of 90 m or 80 m following exercise or oxygen intervention, respectively) when compared to samples that had an upward change in the miRNA marker. These natural animal model and human sample studies further highlight the utility of miRNAs as future biomarkers. The different directional changes of the miRNA markers following supervised exercise training or nightly oxygen intervention could indicate different PAH molecular pathomechanisms (endotypes). Further studies are needed to test this idea.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2018.00955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068281PMC
July 2018

Polymorphonuclear Leukocytes in Pulmonary Hypertension and Fibrosis: Not Always What They Appear to Be.

Am J Respir Cell Mol Biol 2018 02;58(2):135-137

1 Department of Medicine, Division of Pulmonary Medicine New York University School of Medicine New York, New York and.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2017-0336EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806001PMC
February 2018

The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension.

Eur Respir J 2018 01 25;51(1). Epub 2018 Jan 25.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.

Increasing evidence points towards an inflammatory component underlying pulmonary hypertension. However, the conclusive characterisation of multiple inflammatory cell populations in the lung is challenging due to the complexity of marker specificity and tissue inaccessibility. We used an unbiased computational flow cytometry approach to delineate the inflammatory landscape of idiopathic pulmonary arterial hypertension (IPAH) and healthy donor lungs.Donor and IPAH samples were discriminated clearly using principal component analysis to reduce the multidimensional data obtained from single-cell flow cytometry analysis. In IPAH lungs, the predominant CD45 cell type switched from neutrophils to CD3 T-cells, with increases in CD4, CD8 and γδT-cell subsets. Additionally, diversely activated classical myeloid-derived dendritic cells (CD14HLA-DRCD11cCD1a) and nonclassical plasmacytoid dendritic cells (pDCs; CD14CD11cCD123HLA-DR), together with mast cells and basophils, were more abundant in IPAH samples. We describe, for the first time, the presence and regulation of two cell types in IPAH, γδT-cells and pDCs, which link innate and adaptive immunity.With our high-throughput flow cytometry with multidimensional dataset analysis, we have revealed the interactive interplay between multiple inflammatory cells is a crucial part of their integrative network. The identification of γδT-cells and pDCs in this disease potentially provides a missing link between IPAH, autoimmunity and inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01214-2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383570PMC
January 2018

PVDOMICS: A Multi-Center Study to Improve Understanding of Pulmonary Vascular Disease Through Phenomics.

Circ Res 2017 10;121(10):1136-1139

From the Vanderbilt University, Nashville, TN (A.R.H., J.H.N.); Cleveland Clinic, OH (G.J.B., M.A.A., J.B., S.A.A.C., S.C.E., B.H., J.K.L., M.A.O., W.H.W.T.); Wayne State University/John D. Dingell VAMC, Detroil, MI (A.A.); Columbia University, New York, NY (E.B.R., W.K.C.); Mayo Clinic, Rochester, MN (B.A.B., R.P.F.); Pulmonary Hypertension Association, Silver Spring, MD (M.P.G.); New York University Medical Center (G.G.); Johns Hopkins Hospital, Baltimore, MD (P.M.H., S.C.M.); Tufts Medical Center, Boston, MA (N.S.H.); Weill Cornell Medicine, New York, NY (E.M.H.); Brigham and Women's Hospital, Boston, MA (B.A.M., D.M.S., A.B.W., J.A.L.); The University of Arizona, Tucson (F.P.R., J.X.-J.Y.); and National Heart, Lung and Blood Institute, Bethesda, MD (L.X.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.117.311737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685561PMC
October 2017

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease.

EBioMedicine 2016 Nov 24;13:212-224. Epub 2016 Oct 24.

Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, United States. Electronic address:

Gaucher disease (GD), the most common lysosomal storage disease, is caused by mutations in GBA1 encoding of β-glucocerebrosidase (GCase). Recently it was reported that progranulin (PGRN) insufficiency and deficiency associated with GD in human and mice, respectively. However the underlying mechanisms remain unknown. Here we report that PGRN binds directly to GCase and its deficiency results in aggregation of GCase and its receptor LIMP2. Mass spectrometry approaches identified HSP70 as a GCase/LIMP2 complex-associated protein upon stress, with PGRN as an indispensable adaptor. Additionally, 98 amino acids of C-terminal PGRN, referred to as Pcgin, are required and sufficient for the binding to GCase and HSP70. Pcgin effectively ameliorates the disease phenotype in GD patient fibroblasts and animal models. These findings not only demonstrate that PGRN is a co-chaperone of HSP70 and plays an important role in GCase lysosomal localization, but may also provide new therapeutic interventions for lysosomal storage diseases, in particular GD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2016.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264254PMC
November 2016

Aberrant immune response with consequent vascular and connective tissue remodeling - causal to scleroderma and associated syndromes such as Raynaud phenomenon and other fibrosing syndromes?

Curr Opin Rheumatol 2016 Nov;28(6):571-6

aDepartment of Environmental Medicine bDepartment of Medicine, New York University Langone Medical Center, Tuxedo, New York, USA.

Purpose Of Review: Scleroderma and other autoimmune-induced connective tissue diseases are characterized by dysfunctions in the immune system, connective tissue and the vasculature. We are focusing on systemic sclerosis (SSc)-associated pulmonary hypertension, which remains a leading cause of death with only a 50-60% of 2-year survival rate.

Recent Findings: Much research and translational efforts have been directed at understanding the immune response that causes SSc and the networked interactions with the connective tissue and the vasculature. One of the unexpected findings was that in some cases the pathogenic immune response in SSc resembles the immune response to helminth parasites. During coevolution, means of communication were developed which protect the host from over-colonization with parasites and which protect the parasite from excessive host responses. One explanation for the geographically clustered occurrence of SSc is that environmental exposures combined with genetic predisposition turn on triggers of molecular and cellular modules that were once initiated by parasites.

Summary: Future research is needed to further understand the parasite-derived signals that dampen the host response. Therapeutic helminth infection or treatment with parasite-derived response modifiers could be promising new management tools for autoimmune connective tissue diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BOR.0000000000000333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114306PMC
November 2016

Association Between Progranulin and Gaucher Disease.

EBioMedicine 2016 Sep 4;11:127-137. Epub 2016 Aug 4.

Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, United States. Electronic address:

Background: Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of β-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD.

Methods: Serum levels of PGRN were measured from 115 GD patients and 99 healthy controls, whole GRN gene from 40 GD patients was sequenced, and the genotyping of 4 SNPs identified in GD patients was performed in 161 GD and 142 healthy control samples. Development of GD in PGRN-deficient mice was characterized, and the therapeutic effect of rPGRN on GD analyzed.

Findings: Serum PGRN levels were significantly lower in GD patients (96.65±53.45ng/ml) than those in healthy controls of the general population (164.99±43.16ng/ml, p<0.0001) and of Ashkenazi Jews (150.64±33.99ng/ml, p<0.0001). Four GRN gene SNPs, including rs4792937, rs78403836, rs850713, and rs5848, and three point mutations, were identified in a full-length GRN gene sequencing in 40 GD patients. Large scale SNP genotyping in 161 GD and 142 healthy controls was conducted and the four SNP sites have significantly higher frequency in GD patients. In addition, "aged" and challenged adult PGRN null mice develop GD-like phenotypes, including typical Gaucher-like cells in lung, spleen, and bone marrow. Moreover, lysosomes in PGRN KO mice exhibit a tubular-like appearance. PGRN is required for the lysosomal appearance of GCase and its deficiency leads to GCase accumulation in the cytoplasm. More importantly, recombinant PGRN is therapeutic in various animal models of GD and human fibroblasts from GD patients.

Interpretation: Our data demonstrates an unknown association between PGRN and GD and identifies PGRN as an essential factor for GCase's lysosomal localization. These findings not only provide new insight into the pathogenesis of GD, but may also have implications for diagnosis and alternative targeted therapies for GD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5049935PMC
http://dx.doi.org/10.1016/j.ebiom.2016.08.004DOI Listing
September 2016

Challenges and Current Efforts in the Development of Biomarkers for Chronic Inflammatory and Remodeling Conditions of the Lungs.

Biomark Insights 2015 16;10(Suppl 4):59-72. Epub 2016 Feb 16.

Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA.

This review discusses biomarkers that are being researched for their usefulness to phenotype chronic inflammatory lung diseases that cause remodeling of the lung's architecture. The review focuses on asthma, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension. Bio-markers of environmental exposure and specific classes of biomarkers (noncoding RNA, metabolism, vitamin, coagulation, and microbiome related) are also discussed. Examples of biomarkers that are in clinical use, biomarkers that are under development, and biomarkers that are still in the research phase are discussed. We chose to present examples of the research in biomarker development by diseases, because asthma, COPD, and pulmonary hypertension are distinct entities, although they clearly share processes of inflammation and remodeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4137/BMI.S29514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756863PMC
February 2016

Spotlight on Inflammation in Pulmonary Hypertension.

Am J Respir Crit Care Med 2015 Oct;192(8):913-5

1 Department of Environmental Medicine and.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201507-1426EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642212PMC
October 2015

The Effects of Antigen-Specific IgG1 Antibody for the Pulmonary-Hypertension-Phenotype and B Cells for Inflammation in Mice Exposed to Antigen and Fine Particles from Air Pollution.

PLoS One 2015 16;10(6):e0129910. Epub 2015 Jun 16.

Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York, United States of America; Department of Medicine, Division of Pulmonary Medicine, New York University Langone Medical Center, New York, New York, United States of America.

Air pollution is known to exacerbate chronic inflammatory conditions of the lungs including pulmonary hypertension, cardiovascular diseases and autoimmune diseases. Directly pathogenic antibodies bind pro-inflammatory cell receptors and cause or exacerbate inflammation. In contrast, anti-inflammatory antibody isotypes (e.g. mouse immunoglobulin G1, IgG1) bind inhibitory cell receptors and can inhibit inflammation. Our previous studies showed that co-exposure to antigen and urban ambient particulate matter (PM2.5) induced severe pulmonary arterial thickening and increased right ventricular systolic pressures in mice via T-cell produced cytokines, Interleukin (IL)-13 and IL-17A. The aim of the current study was to understand how B cell and antibody responses integrate into this T cell cytokine network for the pulmonary hypertension phenotype. Special focus was on antigen-specific IgG1 that is the predominant antibody in the experimental response to antigen and urban ambient PM2.5. Wild type and B cell-deficient mice were primed with antigen and then challenged with antigen and urban particulate matter and injected with antibodies as appropriate. Our data surprisingly showed that B cells were necessary for the development of increased right ventricular pressures and molecular changes in the right heart in response to sensitization and intranasal challenge with antigen and PM2.5. Further, our studies showed that both, the increase in right ventricular systolic pressure and right ventricular molecular changes were restored by reconstituting the B cell KO mice with antigen specific IgG1. In addition, our studies identified a critical, non-redundant role of B cells for the IL-17A-directed inflammation in response to exposure with antigen and PM2.5, which was not corrected with antigen-specific IgG1. In contrast, IL-13-directed inflammatory markers, as well as severe pulmonary arterial remodeling induced by challenge with antigen and PM2.5 were similar in B cell-deficient and wild type mice. Our studies have identified B cells and antigen specific IgG1 as potential therapeutic targets for pulmonary hypertension associated with immune dysfunction and environmental exposures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129910PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469456PMC
April 2016

Coexpression of type 2 immune targets in sputum-derived epithelial and dendritic cells from asthmatic subjects.

J Allergy Clin Immunol 2015 Sep 23;136(3):619-627.e5. Epub 2015 Mar 23.

Department of Medicine, New York University Langone Medical Center, New York, NY; Department of Environmental Medicine, New York University Langone Medical Center, New York, NY. Electronic address:

Background: Noninvasive sputum sampling has enabled the identification of biomarkers in asthmatic patients. Studies of discrete cell populations in sputum can enhance measurements compared with whole sputum in which changes in rare cells and cell-cell interactions can be masked.

Objective: We sought to enrich for sputum-derived human bronchial epithelial cells (sHBECs) and sputum-derived myeloid type 1 dendritic cells (sDCs) to describe transcriptional coexpression of targets associated with a type 2 immune response.

Methods: A case-control study was conducted with patients with mild asthma (asthmatic cases) and healthy control subjects. Induced sputum was obtained for simultaneous enrichment of sHBECs and sDCs by using flow cytometry. Quantitative PCR was used to measure mRNA for sHBEC thymic stromal lymphopoietin (TSLP), IL33, POSTN, and IL25 and downstream targets in sDCs (OX40 ligand [OX40L], CCL17, PPP1R14A, CD1E, CD1b, CD80, and CD86).

Results: Final analyses for the study sample were based on 11 control subjects and 13 asthmatic cases. Expression of TSLP, IL33, and POSTN mRNA was increased in sHBECs in asthmatic cases (P = .001, P = .05, and P = .04, respectively). Expression of sDC OX40L and CCL17 mRNA was increased in asthmatic cases (P = .003 and P = .0001, respectively). sHBEC TSLP mRNA expression was strongly associated with sDC OX40L mRNA expression (R = 0.65, P = .001) and less strongly with sDC CCL17 mRNA expression. sHBEC IL33 mRNA expression was associated with sDC OX40L mRNA expression (R = 0.42, P = .04) but not sDC CCL17 mRNA expression.

Conclusions: Noninvasive sampling and enrichment of select cell populations from sputum can further our understanding of cell-cell interactions in asthmatic patients with the potential to enhance endotyping of asthmatic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2014.12.1950DOI Listing
September 2015

Interleukin 13- and interleukin 17A-induced pulmonary hypertension phenotype due to inhalation of antigen and fine particles from air pollution.

Pulm Circ 2014 Dec;4(4):654-68

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA ; Pulmonary Medicine, Department of Medicine, New York University School of Medicine, New York, New York, USA.

Pulmonary hypertension has a marked detrimental effect on quality of life and life expectancy. In a mouse model of antigen-induced pulmonary arterial remodeling, we have recently shown that coexposure to urban ambient particulate matter (PM) significantly increased the thickening of the pulmonary arteries and also resulted in significantly increased right ventricular systolic pressures. Here we interrogate the mechanism and show that combined neutralization of interleukin 13 (IL-13) and IL-17A significantly ameliorated the increase in right ventricular systolic pressure, the circumferential muscularization of pulmonary arteries, and the molecular change in the right ventricle. Surprisingly, our data revealed a protective role of IL-17A for the antigen- and PM-induced severe thickening of pulmonary arteries. This protection was due to the inhibition of the effects of IL-13, which drove this response, and the expression of metalloelastase and resistin-like molecule α. However, the latter was redundant for the arterial thickening response. Anti-IL-13 exacerbated airway neutrophilia, which was due to a resulting excess effect of IL-17A, confirming concurrent cross inhibition of IL-13- and IL-17A-dependent responses in the lungs of animals exposed to antigen and PM. Our experiments also identified IL-13/IL-17A-independent molecular reprogramming in the lungs induced by exposure to antigen and PM, which indicates a risk for arterial remodeling and protection from arterial constriction. Our study points to IL-13- and IL-17A-coinduced inflammation as a new template for biomarkers and therapeutic targeting for the management of immune response-induced pulmonary hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/678511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278625PMC
December 2014

Perspective: ambient air pollution: inflammatory response and effects on the lung's vasculature.

Pulm Circ 2014 Mar;4(1):25-35

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.

Particulates from air pollution are implicated in causing or exacerbating respiratory and systemic cardiovascular diseases and are thought to be among the leading causes of morbidity and mortality. However, the contribution of ambient particulate matter to diseases affecting the pulmonary circulation, the right heart, and especially pulmonary hypertension is much less documented. Our own work and that of other groups has demonstrated that prolonged exposure to antigens via the airways can cause severe pulmonary arterial remodeling. In addition, vascular changes have been well documented in a typical disease of the airways, asthma. These experimental and clinical findings link responses in the airways with responses in the lung's vasculature. It follows that particulate air pollution could cause, or exacerbate, diseases in the pulmonary circulation and associated pulmonary hypertension. This perspective details the literature for support of this concept. Data regarding the health effects of particulate matter from air pollution on the lung's vasculature, with emphasis on the lung's inflammatory responses to particulate matter deposition and pulmonary hypertension, are discussed. A deeper understanding of the health implications of exposure to ambient particulate matter will improve our knowledge of how to improve the management of lung diseases, including diseases of the pulmonary circulation. As man-made ambient particulate air pollution is typically linked to economic growth, a better understanding of the health effects of exposure to particulate air pollution is expected to integrate the global goal of achieving healthy living for all.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/674902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070766PMC
March 2014

Dust events, pulmonary diseases and immune system.

Am J Clin Exp Immunol 2014 27;3(1):20-9. Epub 2014 Feb 27.

Departmentof Environmental Medicine, New York University School of Medicine Tuxedo, New York, USA ; Division of Pulmonary Medicine, Department of Medicine, New York University School of Medicine New York, USA.

Incidences of sand storms have increased in recent years and there is evidence that these dusts can move across long distances. Sand dusts have different adverse effects on health, but one of the most important of them is pulmonary disease. After inhalation of dust, many dust particles are moved to the airways. Dust particles can be sensed by airways epithelial cells, activate macrophages, dendritic cells and innate immune cells and then initiate responses in various populations of specific immune cells such as T helper cells subsets (Th1, Th2, Th17), T cytotoxic cells and B cells. Initiation of inflammatory immune responses, activation of immune cells and releases of many cytokines, chemokines and other inflammatory molecules, have variable pathologic affects on lung in different respiratory diseases. Unfortunately control of desert dusts is more difficult than control of air pollution. For prevention and treatment of respiratory diseases that are caused by desert dusts, researchers need well-designed epidemiological studies, combined with analysis of the precise composition of sand dusts, and the precise mechanisms of the immune responses. Recognizing the exact cellular and molecular immune mechanisms would be very useful to find new approaches for treatment of desert dust associated pulmonary diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960758PMC
June 2014

Short-term inhalation of cadmium oxide nanoparticles alters pulmonary dynamics associated with lung injury, inflammation, and repair in a mouse model.

Inhal Toxicol 2014 Jan;26(1):48-58

Department of Environmental Medicine, New York University School of Medicine , Tuxedo, NY , USA and.

Context: Cadmium oxide nanoparticles (CdO NPs) are employed in optoelectronic devices and as a starting material for generating quantum dots as well as for medical imaging and targeting of pharmaceutical agents to disease sites. However, there are lack of data concerning short- and long-term effects of CdO NPs on the lungs.

Objective: To determine the effects of inhaled CdO NPs at an occupationally relevant concentration on pulmonary injury and repair, and on systemic immunity in adult male mice.

Methods: Mice were exposed to 240 μg CdO NPs/m(3) for seven days (3 h/d) and lavage levels of pulmonary injury/inflammatory markers, bacterial uptake by circulating phagocytes, and lung histology examined either one or seven days following the final exposure.

Results: Levels of total protein, lactate dehydrogenase activity, cytokine markers of inflammation (i.e. interleukin-1β, tumor necrosis factor-α, and interferon-γ), tissue remodeling matrix metalloproteinases (MMP)-2 and -9 activity, and phagocytic activity of circulating phagocytes were significantly increased one day after the final exposure. By seven days post-exposure, MMP-2 activity decreased to control levels, while MMP-9 activity remained significantly above control values, although dropping by about half from day one.

Conclusions: This study demonstrates that short-term inhalation exposure to CdO NPs can stimulate pathways in the lungs associated with inflammation, cell injury, and tissue remodeling as well as alter immune function. Findings here demonstrate that even short-term inhalation exposure to CdO NPs in the workplace could lead to deleterious pulmonary effects in exposed workers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/08958378.2013.851746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041479PMC
January 2014

T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia.

J Immunol 2013 Sep 21;191(6):3100-11. Epub 2013 Aug 21.

Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.

Th17 cells are a proinflammatory subset of effector T cells that have been implicated in the pathogenesis of asthma. Their production of the cytokine IL-17 is known to induce local recruitment of neutrophils, but the direct impact of IL-17 on the lung epithelium is poorly understood. In this study, we describe a novel mouse model of spontaneous IL-17-driven lung inflammation that exhibits many similarities to asthma in humans. We have found that STAT3 hyperactivity in T lymphocytes causes an expansion of Th17 cells, which home preferentially to the lungs. IL-17 secretion then leads to neutrophil infiltration and lung epithelial changes, in turn leading to a chronic inflammatory state with increased mucus production and decreased lung function. We used this model to investigate the effects of IL-17 activity on airway epithelium and identified CXCL5 and MIP-2 as important factors in neutrophil recruitment. The neutralization of IL-17 greatly reduces pulmonary neutrophilia, underscoring a key role for IL-17 in promoting chronic airway inflammation. These findings emphasize the role of IL-17 in mediating neutrophil-driven pulmonary inflammation and highlight a new mouse model that may be used for the development of novel therapies targeting Th17 cells in asthma and other chronic pulmonary diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1301360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822005PMC
September 2013

Interleukin 13 and the evolution of asthma therapy.

Am J Clin Exp Immunol 2012 Jun;1(1):20-27

Departments of Environmental Medicine and Medicine, NYU Langone Medical Center, Tuxedo, NY 10987.

This is a concise review on Interleukin (IL)-13 and the evolution of asthma therapy, from discovery of the molecule, the identification of its pathogenic role in animal models of asthma, to the development of clinically successful neutralizing agents. The translational path from basic research to clinical application was not sequential as expected but random with respect to the tools (molecular & cell biology, animal models, human studies) used and to the application of academic versus industry research. The experiences with the development of neutralizing anti-IL-13 reagents emphasize the need for inclusion of a biomarker assay in the clinical trials that both identifies individuals that actually have aberrant expression of the pathway of interest and allows determining whether the target of interest is neutralized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630076PMC
June 2012

MicroRNA-375 regulation of thymic stromal lymphopoietin by diesel exhaust particles and ambient particulate matter in human bronchial epithelial cells.

J Immunol 2013 Apr 1;190(7):3757-63. Epub 2013 Mar 1.

Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.

Air pollution contributes to acute exacerbations of asthma and the development of asthma in children and adults. Airway epithelial cells interface innate and adaptive immune responses, and have been proposed to regulate much of the response to pollutants. Thymic stromal lymphopoietin (TSLP) is a pivotal cytokine linking innate and Th2 adaptive immune disorders, and is upregulated by environmental pollutants, including ambient particulate matter (PM) and diesel exhaust particles (DEP). We show that DEP and ambient fine PM upregulate TSLP mRNA and human microRNA (hsa-miR)-375 in primary human bronchial epithelial cells (pHBEC). Moreover, transfection of pHBEC with anti-hsa-miR-375 reduced TSLP mRNA in DEP but not TNF-α-treated cells. In silico pathway evaluation suggested the aryl hydrocarbon receptor (AhR) as one possible target of miR-375. DEP and ambient fine PM (3 μg/cm(2)) downregulated AhR mRNA. Transfection of mimic-hsa-miR-375 resulted in a small downregulation of AhR mRNA compared with resting AhR mRNA. AhR mRNA was increased in pHBEC treated with DEP after transfection with anti-hsa-miR-375. Our data show that two pollutants, DEP and ambient PM, upregulate TSLP in human bronchial epithelial cells by a mechanism that includes hsa-miR-375 with complex regulatory effects on AhR mRNA. The absence of this pathway in TNF-α-treated cells suggests multiple regulatory pathways for TSLP expression in these cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1201165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665109PMC
April 2013

Modification of hemodynamic and immune responses to exposure with a weak antigen by the expression of a hypomorphic BMPR2 gene.

PLoS One 2013 29;8(1):e55180. Epub 2013 Jan 29.

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America.

Background: Hypomorphic mutations in the bone morphogenic protein receptor (BMPR2) confer a much greater risk for developing pulmonary arterial hypertension (PAH). However, not all carriers of a mutation in the BMPR2 gene suffer from PAH. We have previously shown that prolonged T helper 2 (Th2) responses in the lungs to a mild antigen delivered via the airways induce severe pulmonary arterial remodeling, but no pulmonary hypertension. The current studies were designed to test the idea that Th2 responses to a mild antigen together with the expression of a hypomorphic BMPR2 gene would trigger pulmonary hypertension.

Methodology/principal Findings: Mice that expressed a hypomorphic BMPR2 transgene (transgene-positive) and transgene-negative mice were either exposed to saline, or primed and exposed to a mild antigen (Ovalbumin) over a prolonged period of time. Only transgene-positive but not transgene-negative mice exposed to antigen developed significantly increased right ventricular systolic pressures, while both groups showed pulmonary artery remodeling with severe muscularization and airway inflammation to a similar degree. Antigen exposure resulted in a smaller increase in the percentage of Interleukin (IL)-13 positive T cells in the lymph nodes, and in a smaller increase in resistin-like-molecule (RELM)α expression and a decreased ratio of expression of IL-33 relative to its receptor (IL-1-receptor-like 1, IL1RL1-ST2) in the right ventricles of transgene-positive mice compared to transgene-negative animals. Furthermore, only antigen-challenged transgene-positive mice showed a significant increase in Interferon (IFN)γ positive T cells over saline-exposed controls.

Conclusions/significance: Our study suggests that exposure with a mild Th2 antigen can trigger pulmonary hypertension on the background of the expression of a hypomorphic BMPR2 gene and that conversely, the expression of the hypomorphic BMPR2 gene can alter the immune response to a mild, inhaled antigen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055180PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558423PMC
July 2013

Right ventricular systolic pressure measurements in combination with harvest of lung and immune tissue samples in mice.

J Vis Exp 2013 Jan 16(71):e50023. Epub 2013 Jan 16.

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, USA.

The function of the right heart is to pump blood through the lungs, thus linking right heart physiology and pulmonary vascular physiology. Inflammation is a common modifier of heart and lung function, by elaborating cellular infiltration, production of cytokines and growth factors, and by initiating remodeling processes. Compared to the left ventricle, the right ventricle is a low-pressure pump that operates in a relatively narrow zone of pressure changes. Increased pulmonary artery pressures are associated with increased pressure in the lung vascular bed and pulmonary hypertension. Pulmonary hypertension is often associated with inflammatory lung diseases, for example chronic obstructive pulmonary disease, or autoimmune diseases. Because pulmonary hypertension confers a bad prognosis for quality of life and life expectancy, much research is directed towards understanding the mechanisms that might be targets for pharmaceutical intervention. The main challenge for the development of effective management tools for pulmonary hypertension remains the complexity of the simultaneous understanding of molecular and cellular changes in the right heart, the lungs and the immune system. Here, we present a procedural workflow for the rapid and precise measurement of pressure changes in the right heart of mice and the simultaneous harvest of samples from heart, lungs and immune tissues. The method is based on the direct catheterization of the right ventricle via the jugular vein in close-chested mice, first developed in the late 1990s as surrogate measure of pressures in the pulmonary artery. The organized team-approach facilitates a very rapid right heart catheterization technique. This makes it possible to perform the measurements in mice that spontaneously breathe room air. The organization of the work-flow in distinct work-areas reduces time delay and opens the possibility to simultaneously perform physiology experiments and harvest immune, heart and lung tissues. The procedural workflow outlined here can be adapted for a wide variety of laboratory settings and study designs, from small, targeted experiments, to large drug screening assays. The simultaneous acquisition of cardiac physiology data that can be expanded to include echocardiography and harvest of heart, lung and immune tissues reduces the number of animals needed to obtain data that move the scientific knowledge basis forward. The procedural workflow presented here also provides an ideal basis for gaining knowledge of the networks that link immune, lung and heart function. The same principles outlined here can be adapted to study other or additional organs as needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/50023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582655PMC
January 2013

Interleukin-19: a constituent of the regulome that controls antigen presenting cells in the lungs and airway responses to microbial products.

PLoS One 2011 15;6(11):e27629. Epub 2011 Nov 15.

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America.

Background: Interleukin (IL)-19 has been reported to enhance chronic inflammatory diseases such as asthma but the in vivo mechanism is incompletely understood. Because IL-19 is produced by and regulates cells of the monocyte lineage, our studies focused on in vivo responses of CD11c positive (CD11c+) alveolar macrophages and lung dendritic cells.

Methodology/principal Findings: IL-19-deficient (IL-19-/-) mice were studied at baseline (naïve) and following intranasal challenge with microbial products, or recombinant cytokines. Naïve IL-19-/- mixed background mice had a decreased percentage of CD11c+ cells in the bronchoalveolar-lavage (BAL) due to the deficiency in IL-19 and a trait inherited from the 129-mouse strain. BAL CD11c+ cells from fully backcrossed IL-19-/- BALB/c or C57BL/6 mice expressed significantly less Major Histocompatibility Complex class II (MHCII) in response to intranasal administration of lipopolysaccharide, Aspergillus antigen, or IL-13, a pro-allergic cytokine. Neurogenic-locus-notch-homolog-protein-2 (Notch2) expression by lung monocytes, the precursors of BAL CD11c+ cells, was dysregulated: extracellular Notch2 was significantly decreased, transmembrane/intracellular Notch2 was significantly increased in IL-19-/- mice relative to wild type. Instillation of recombinant IL-19 increased extracellular Notch2 expression and dendritic cells cultured from bone marrow cells in the presence of IL-19 showed upregulated extracellular Notch2. The CD205 positive subset among the CD11c+ cells was 3-5-fold decreased in the airways and lungs of naïve IL-19-/- mice relative to wild type. Airway inflammation and histological changes in the lungs were ameliorated in IL-19-/- mice challenged with Aspergillus antigen that induces T lymphocyte-dependent allergic inflammation but not in IL-19-/- mice challenged with lipopolysaccharide or IL-13.

Conclusions/significance: Because MHCII is the molecular platform that displays peptides to T lymphocytes and Notch2 determines cell fate decisions, our studies suggest that endogenous IL-19 is a constituent of the regulome that controls both processes in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0027629PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217014PMC
March 2012

Exposure to inhaled nickel nanoparticles causes a reduction in number and function of bone marrow endothelial progenitor cells.

Inhal Toxicol 2010 Dec 11;22 Suppl 2:95-9. Epub 2010 Oct 11.

Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.

Introduction: Particulate matter (PM), specifically nickel (Ni) found on or in PM, has been associated with an increased risk of mortality in human population studies and significant increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone, and potentiated atherosclerosis in murine exposures. Recently, murine inhalation of Ni nanoparticles have been shown to cause pulmonary inflammation that affects cardiovascular tissue and potentiates atherosclerosis. These adverse cardiovascular outcomes may be due to the effects of Ni on endothelial progenitor cells (EPCs), endogenous semi-pluripotent stem cells that aid in endothelial repair. Thus, we hypothesize that Ni nanoparticle exposures decrease cell count and cause impairments in function that may ultimately have significant effects on various cardiovascular diseases, such as, atherosclerosis.

Methods: Experiments involving inhaled Ni nanoparticle exposures (2 days/5 h/day at ∼1200 µg/m(3), 3 days/5 h/day at ∼700 µg/m(3), and 5 days/5 h/day at ∼100 µg/m(3)), were performed in order to quantify bone marrow resident EPCs using flow cytometry in C57BL/6 mice. Plasma levels of human stromal cell-derived factor 1α (SDF-1α) and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assay and in vitro functional assessments of cultured EPCs were conducted.

Results And Conclusions: Significant EPC count differences between exposure and control groups for Ni nanoparticle exposures were observed. Differences in EPC tube formation and chemotaxis were also observed for the Ni nanoparticle exposed group. Plasma VEGF and SDF-1α differences were not statistically significant. In conclusion, this study shows that inhalation of Ni nanoparticles results in functionally impaired EPCs and reduced number in the bone marrow, which may lead to enhanced progression of atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/08958378.2010.515269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887278PMC
December 2010

Prenatal allergen and diesel exhaust exposure and their effects on allergy in adult offspring mice.

Allergy Asthma Clin Immunol 2010 May 11;6(1). Epub 2010 May 11.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.

Background: Multiple studies have suggested that prenatal exposure to either allergens or air pollution may increase the risk for the development of allergic immune responses in young offspring. However, the effects of prenatal environmental exposures on adult offspring have not been well-studied. We hypothesized that combined prenatal exposure to Aspergillus fumigatus (A. fumigatus) allergen and diesel exhaust particles will be associated with altered IgE production, airway inflammation, airway hyperreactivity (AHR), and airway remodeling of adult offspring.

Methods: Following sensitization via the airway route to A. fumigatus and mating, pregnant BALB/c mice were exposed to additional A. fumigatus and/or diesel exhaust particles. At age 9-10 weeks, their offspring were sensitized and challenged with A. fumigatus.

Results: We found that adult offspring from mice that were exposed to A. fumigatus or diesel exhaust particles during pregnancy experienced decreases in IgE production. Adult offspring of mice that were exposed to both A. fumigatus and diesel exhaust particles during pregnancy experienced decreases in airway eosinophilia.

Conclusion: These results suggest that, in this model, allergen and/or diesel administration during pregnancy may be associated with protection from developing systemic and airway allergic immune responses in the adult offspring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1710-1492-6-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875211PMC
May 2010

Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression.

J Immunol 2008 Aug;181(4):2338-47

The Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

T cell-specific deletion of Blimp-1 causes abnormal T cell homeostasis and function, leading to spontaneous, fatal colitis in mice. Herein we explore the role of Blimp-1 in Th1/Th2 differentiation. Blimp-1 mRNA and protein are more highly expressed in Th2 cells compared with Th1 cells, and Blimp-1 attenuates IFN-gamma production in CD4 cells activated under nonpolarizing conditions. Although Blimp-1-deficient T cells differentiate normally to Th2 cytokines in vitro, Blimp-1 is required in vivo for normal Th2 humoral responses to NP-KLH (4-hydroxy-3-nitrophenylacetyl/keyhole lymphocyte hemocyanin) immunization. Lack of Blimp-1 in CD4 T cells causes increased IFN-gamma, T-bet, and Bcl-6 mRNA. By chromatin immunoprecipitation we show that Blimp-1 binds directly to a distal regulatory region in the ifng gene and at multiple sites in tbx21 and bcl6 genes. Our data provide evidence that Blimp-1 functions in Th2 cells to reinforce Th2 differentiation by repressing critical Th1 genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.181.4.2338DOI Listing
August 2008

Pulmonary arterial remodeling induced by a Th2 immune response.

J Exp Med 2008 Feb 28;205(2):361-72. Epub 2008 Jan 28.

St. Luke's Roosevelt Hospital, New York, NY 10019, USA.

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4(+) T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule alpha, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20071008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271018PMC
February 2008

Time-dependent alterations in gene expression of interleukin-8 in the bronchial epithelium of horses with recurrent airway obstruction.

Am J Vet Res 2006 Apr;67(4):669-77

Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

Objective: To evaluate time-dependent alterations in gene expression of chemokines in bronchial epithelium of recurrent airway obstruction (RAO)-affected horses and whether alterations resulted from increases in gene expression of interleukin (IL)-17 in cells isolated from bronchoalveolar lavage fluid (BALF).

Animals: 8 RAO-susceptible horses and 9 control horses.

Procedure: In 2 experiments, both groups of horses were evaluated after being maintained on pasture and after being stabled and fed dusty hay for 1, 14, 35, and 49 days (experiment 1) or 14 and 28 days (experiment 2). In experiment 1, gene expression of IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and Toll-like receptor 4 (TLR4) in epithelium and IL-8, IL-17, and TLR4 in BALF cells was measured. In experiment 2, bronchial biopsy specimens were evaluated for IL-8 immunoreactivity.

Results: In RAO-susceptible horses after 14 days of challenge exposure, there was a 3- and 10-fold increase in gene expression of IL-8 for epithelial and BALF cells and an increase in IL-8 immunoreactivity in epithelial cells. Challenge exposure failed to alter gene expression of CXCL1, GM-CSF, G-CSF, and TLR4 in epithelial cells of any horses at any time point. During challenge exposure, gene expression of BALF cell IL-17 was downregulated in control horses (day 1) and upregulated in RAO-affected horses (day 35).

Conclusions And Clinical Relevance: Epithelial-derived IL-8 may promote airway neutrophilia, but the inciting stimulus is unlikely to be IL-17 because upregulation of this gene is subsequent to that of IL-8 in epithelial cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2460/ajvr.67.4.669DOI Listing
April 2006
-->