Seamas C Donnelly

Publications of Seamas C Donnelly

• Macrophage Migration Inhibitory Factor Enzymatic Activity, Lung Inflammation and Cystic Fibrosis.

  Authors: Huzaifa Adamali, Michelle E Armstrong, Anne Marie McLaughlin, Gordon Cooke, Edward McKone, Christine M Costello, Charles G Gallagher, Lin Leng, John A Baugh, Günter Fingerle-Rowson, Richard J Bucala, Paul McLoughlin, Seamas C Donnelly

  American journal of respiratory and critical care medicine. 05/2012;

  RATIONALE: Macrophage migration inhibitory factor (MIF) is a pro-inflammatorymediator with unique tautomerase enzymatic activity; the precise function has notbeen clearly defined. We previouslyRATIONALE: Macrophage migration inhibitory factor (MIF) is a pro-inflammatorymediator with unique tautomerase enzymatic activity; the precise function has notbeen clearly defined. We previously demonstrated that individual CF patients that are genetically predisposed to be high MIF producers develop accelerated end organ injury. OBJECTIVES: To characterize the effects of the MIF-CATT polymorphism in CFpatients ex vivo. To investigate the role of MIF's tautomerase activity in a murinemodel of Pseudomonas aeruginosa infection. METHODS: MIF and TNF-α protein levels were assessed in plasma or PBMCsupernatants by ELISA. A murine pulmonary model of chronic Pseudomonasinfection was utilized in MIF wild-type mice (mif+/+) and in tautomerase-null, MIFgene knock-in mice (mif P1G/P1G). MEASUREMENTS: MIF protein was measured in plasma and PBMCs from 5- and 6-CATT CF patients; LPS-induced TNF-α production from PBMCs was also assessed.The effect of a specific inhibitor of MIF-tautomerase activity, ISO-1, was investigated in PBMCs. In the murine infection model, total weight loss, differential cell counts, bacterial load and intra-acinar airspace/tissue volume was measured. RESULTS: MIF and TNF-α levels were increased in 6-CATT compared with 5-CATTCF patients. LPS-induced TNF-α production from PBMCs was attenuated in thepresence of ISO-1. In a murine model of Pseudomonas infection, significantly lesspulmonary inflammation and bacterial load was observed in mif P1G/P1G compared with mif+/+ mice. CONCLUSIONS: MIF-tautomerase activity may provide a novel therapeutic target inpatients with chronic inflammatory diseases such as CF, particularly those patientswho are genetically predisposed to produce increased levels of this cytokine.

• Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population.

  Authors: Imran Haq, Sally Chappell, Simon R Johnson, Juzer Lotya, Leslie Daly, Kevin Morgan, Tamar Guetta-Baranes, Josep Roca, Roberto Rabinovich, Ann B Millar, Seamas C Donnelly, Vera Keatings, William MacNee, Jan Stolk, Pieter S Hiemstra, Massimo Miniati, Simonetta Monti, Clare M O'Connor, Noor Kalsheker

  BMC medical genetics. 01/2010; 11:7.

  Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. TheseGenetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

• Proteomics and the lung: Analysis of bronchoalveolar lavage fluid.

  Authors: Praveen Govender, Michael J Dunn, Seamas C Donnelly

  Proteomics. Clinical applications. 09/2009; 3(9):1044-51.

  Our knowledge of the complex bronchoalveolar lavage fluid (BALF) proteome has increased significantly over the last decade; but still, there remain many aspects of the BALF proteome that needOur knowledge of the complex bronchoalveolar lavage fluid (BALF) proteome has increased significantly over the last decade; but still, there remain many aspects of the BALF proteome that need characterization. Current proteomic methodologies resolve proteins within limited dynamic ranges: thereby, being limited in their ability to examine important areas of the BALF proteome, such as low molecular weight, low abundance proteins. To ensure proper coverage of these proteins in the BALF proteome, a refined 2-DE standard operation protocol is presented, highlighting important issues in sample collection, sample preparation, and 2-D DIGE analysis. It is hoped that this will help advance the field of BALF proteomics, BALFomics, which has lagged behind similar biofluids such as plasma and serum.

• Macrophage migration inhibitory factor (MIF), enzymatic activity and the inflammatory response.

  Authors: Gordon Cooke, Michelle E Armstrong, Seamas C Donnelly

  BioFactors (Oxford, England). 04/2009;

  Macrophage migration inhibitory factor represents a key cytokine in human diseases. It plays an important role in both innate and acquired immunity and has been shown to be a key mediator ofMacrophage migration inhibitory factor represents a key cytokine in human diseases. It plays an important role in both innate and acquired immunity and has been shown to be a key mediator of inflammatory diseases. More recently MIF has been implicated in cancer pathogenesis. Over the decades its structure and functions have been elucidated and this has led to it being further classified as a hormone and an enzyme. It has isomerase enzymatic activity and increasing evidence implicates this activity in inflammatory disease. Consequently, there is increasing interest in developing small molecular weight inhibitors which could target this novel enzymatic activity in disease. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

• Diagnosis of heart failure with preserved ejection fraction: improved accuracy with the use of markers of collagen turnover.

  Authors: Ramón Martos, John Baugh, Mark Ledwidge, Christina O'Loughlin, Niamh F Murphy, Carmel Conlon, Anil Patle, Seamas C Donnelly, Kenneth McDonald

  European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology. 02/2009; 11(2):191-7.

  AIMS: Heart failure with preserved ejection fraction (HF-PEF) can be difficult to diagnose in clinical practice. Myocardial fibrosis is a major determinant of diastolic dysfunction (DD), potentiallyAIMS: Heart failure with preserved ejection fraction (HF-PEF) can be difficult to diagnose in clinical practice. Myocardial fibrosis is a major determinant of diastolic dysfunction (DD), potentially contributing to the progression of HF-PEF. The aim of this study was to analyse whether serological markers of collagen turnover may predict HF-PEF and DD. METHODS AND RESULTS: We included 85 Caucasian treated hypertensive patients (DD n = 65; both DD and HF-PEF n = 32). Serum carboxy (PICP), amino (PINP), and carboxytelo (CITP) peptides of procollagen type I, amino (PIIINP) peptide of procollagen type III, matrix metalloproteinases (MMP-1, MMP-2, and MMP-9), and tissue inhibitor of MMP levels were assayed. Using receiver operating characteristic curve analysis, MMP-2 (AUC = 0.91; 95% CI: 0.84, 0.98), CITP (0.83; 0.72, 0.92), PICP (0.82; 0.72, 0.92), B-type natriuretic peptide (BNP) (0.82; 0.73, 0.91), MMP-9 (0.79; 0.68, 0.89), and PIIINP (0.78; 0.66, 0.89) levels were significant predictors of HF-PEF (P < 0.01 for all). Carboxytelo peptides of procollagen type I (AUC = 0.74; 95% CI: 0.62, 0.86), MMP-2 (0.73; 0.62, 0.84), PIIINP (0.73; 0.60, 0.85), BNP (0.69; 0.55, 0.83) and PICP (0.66; 0.54, 0.78) levels were significant predictors of DD (P < 0.05 for all). A cutoff of 1585 ng/mL for MMP-2 provided 91% sensitivity and 76% specificity for predicting HF-PEF and combinations of biomarkers could be used to adjust either sensitivity or specificity. CONCLUSION: Markers of collagen turnover identify patients with HF-PEF and DD. Matrix metalloproteinase 2 may be more useful than BNP in the identification of HF-PEF. This suggests that these new biochemical tools may assist in identifying patients with these diagnostically challenging conditions.

• Small interfering RNAs induce macrophage migration inhibitory factor production and proliferation in breast cancer cells via a double-stranded RNA-dependent protein kinase-dependent mechanism.

  Authors: Michelle E Armstrong, Michael Gantier, Lili Li, Wen Y Chung, Amanda McCann, John A Baugh, Seamas C Donnelly

  Journal of immunology (Baltimore, Md. : 1950). 06/2008; 180(11):7125-33.

  Small interfering RNAs (siRNAs) represent a novel tool to induce gene silencing in mammalian cells and clinical trials are currently ongoing to assess the therapeutic efficacy of siRNAs in variousSmall interfering RNAs (siRNAs) represent a novel tool to induce gene silencing in mammalian cells and clinical trials are currently ongoing to assess the therapeutic efficacy of siRNAs in various human diseases, including age-related macular degeneration and respiratory syncytial virus infection. However, previously reported off-target, nonspecific effects of siRNAs, including activation of type I IFNs and proinflammatory cytokines, remain an outstanding concern regarding use of these agents in vivo. Macrophage-migration inhibitory factor (MIF) is a pleiotropic cytokine with well-described roles in cell proliferation, tumorigenesis, and angiogenesis and represents a target gene for siRNA-based therapy in the treatment of breast cancer. However, in this study we describe an increase in MIF production from mammary adenocarcinoma (MCF-7) cells following transfection with MIF siRNA and various control siRNAs. This effect was shown to be dose-dependent and was attenuated in the presence of a double-stranded RNA-dependent protein kinase inhibitor, 2-aminopurine. Furthermore, treatment of MCF-7 cells with poly(I:C) also stimulated a PKR-dependent increase in MIF production from MCF-7 cells. The biological consequence of the siRNA-induced increase in MIF production from MCF-7 cells was a PKR-dependent increase in proliferation of breast cancer cells. Furthermore, in cDNAs prepared from a primary human breast cancer cohort, we demonstrated a significant correlation (Spearman rank correlation coefficient, r = 0.50, p < 0.0001, n = 63) between PKR- and MIF-mRNA expression. In conclusion, this study highlights the potential biological consequences of off-target, nonspecific effects of siRNAs and underlines the safety concerns regarding the use of siRNAs in the treatment of human diseases, such as cancer.

• A role for macrophage migration inhibitory factor in the neonatal respiratory distress syndrome.

  Authors: Katharine A Kevill, Vineet Bhandari, Mika Kettunen, Lin Leng, Juan Fan, Yuka Mizue, James D Dzuira, Miguel Reyes-Mugica, Courtney L McDonald, John A Baugh, Christine L O'Connor, Zubair H Aghai, Seamas C Donnelly, Alia Bazzy-Asaad, Richard J Bucala

  Journal of immunology (Baltimore, Md. : 1950). 01/2008; 180(1):601-8.

  Using a mouse model of neonatal respiratory distress syndrome (RDS), we demonstrate a central role for macrophage migration inhibitory factor (MIF) in lung maturation at the developmental stage whenUsing a mouse model of neonatal respiratory distress syndrome (RDS), we demonstrate a central role for macrophage migration inhibitory factor (MIF) in lung maturation at the developmental stage when human neonates are most susceptible to RDS. We prematurely delivered mouse pups at embryonic day 18, during the early saccular stage of pulmonary development. Only 8% of the prematurely delivered pups genetically deficient in MIF survived 8 h vs 75% of wild-type controls (p<0.001). This phenotype was corrected when pups of all genotypes were bred from dams heterozygote for MIF deficiency. Local production of MIF in the lung increased at embryonic day 18, continued until full-term at embryonic day 19.5, and decreased in adulthood, thus coinciding with this developmental window. The lungs of pups genetically deficient in MIF were less mature upon histological evaluation, and demonstrated lower levels of vascular endothelial growth factor and corticosterone--two factors that promote fetal lung maturation. In vitro studies support a role for MIF in surfactant production by pulmonary epithelial cells. In a cohort of human neonates with RDS, higher intrapulmonary MIF levels were associated with a lower likelihood of developing bronchopulmonary dysplasia, a sequelae of RDS (p<0.03). This study demonstrates for the first time a role for MIF in lung maturation, and supports a protective role for MIF in newborn lung disease.

• Nuclear transcription of long hairpin RNA triggers innate immune responses.

  Authors: Michael P Gantier, John A Baugh, Seamas C Donnelly

  Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 10/2007; 27(9):789-97.

  RNA interference (RNAi) is one of the most promising tools for deciphering the human genome and has great therapeutic potential. However, its high target specificity limits its efficiency forRNA interference (RNAi) is one of the most promising tools for deciphering the human genome and has great therapeutic potential. However, its high target specificity limits its efficiency for therapeutic protection from viruses with high rates of genetic mutation. This limitation may be overcome by the expression of long hairpin RNAs (lhRNAs). Indeed, lhRNAs have been shown recently to have increased efficacy over short interfering RNAs (siRNAs) as protective antiviral agents. Here, we investigate the expression of lhRNAs and demonstrate unintended effects. We show that overexpressed lhRNAs are exported to the cytoplasm. As a consequence, we detect activation of innate immune signaling pathways by lhRNAs. With growing concerns about the complexity of cytoplasmic detection of dsRNAs by the innate immune machinery, this work highlights the need for closer scrutiny when using lhRNAs as potential antiviral agents.

• Airway nitric oxide output is reduced in bronchiectasis.

  Authors: Susan C Foley, Natalie O Hopkins, Muiris X FitzGerald, Seamas C Donnelly, Paul McLoughlin

  Respiratory medicine. 08/2007; 101(7):1549-55.

  BACKGROUND: Increased concentrations of exhaled nitric oxide (NO) have been detected in inflammatory lung diseases including asthma and have been attributed to increased expression and activity ofBACKGROUND: Increased concentrations of exhaled nitric oxide (NO) have been detected in inflammatory lung diseases including asthma and have been attributed to increased expression and activity of inducible nitric oxide synthase (iNOS) within the airways. However, previous studies of exhaled NO in patients with bronchiectasis have yielded conflicting results, with reports of both increased and normal NO values. Recent evidence from animal models suggests that chronic airway infection reduces NO production within the lung, despite causing increased iNOS expression. We tested the hypothesis that, in human subjects with bronchiectasis, chronic airway infection reduces NO output from the conducting airways. METHODS: Using a recently described two-compartment model, we measured separately the contributions of the conducting airways and the alveoli to exhaled NO in nine patients with stable bronchiectasis and eight control subjects before and after inhaled glucocorticoid therapy. RESULTS: We found that airway NO output was significantly lower in bronchiectasis than in normal airways whereas NO output from the alveoli was similar to that of control subjects. High-dose inhaled glucocorticoid therapy did not alter airway or alveolar NO production. CONCLUSIONS: These findings demonstrate that, in patients with bronchiectasis, airway NO output is reduced and that iNOS does not contribute significantly to airway NO production.

• Role of proteomics in the investigation of pulmonary fibrosis.

  Authors: Praveen Govender, John A Baugh, Stephen R Pennington, Michael J Dunn, Seamas C Donnelly

  Expert review of proteomics. 07/2007; 4(3):379-88.

  Pulmonary fibrosis arises as a consequence of aberrant remodeling and defective repair mechanisms within the lung. This destructive process is the cause of much of the morbidity and mortality in manyPulmonary fibrosis arises as a consequence of aberrant remodeling and defective repair mechanisms within the lung. This destructive process is the cause of much of the morbidity and mortality in many pulmonary disorders. Unfortunately, therapeutic options are limited. A significant advancement in the management of patients with pulmonary fibrosis would be the identification of biomarkers for diagnosis, prognosis and prediction of patient response to therapy. Bronchoalveolar lavage is an ideal tissue target for the discovery of these potential biomarkers in pulmonary fibrosis. Integrative approaches using both gel- and mass spectrometry-based proteomic workflows will allow full coverage of this complex proteome, thereby unlocking this potential information as a clinical tool to aid diagnosis and guide treatment for individual patients with pulmonary fibrosis.

• Macrophage migration inhibitory factor: a probable link between inflammation and cancer.

  Authors: Richard Bucala, Seamas C Donnelly

  Immunity. 04/2007; 26(3):281-5.

  The pleiotropic effects of macrophage migration inhibitory factor (MIF) place it in a central position in the immunopathogenesis of many diseases. Here we discuss the current understanding of MIF'sThe pleiotropic effects of macrophage migration inhibitory factor (MIF) place it in a central position in the immunopathogenesis of many diseases. Here we discuss the current understanding of MIF's role and highlight it as a potential link between inflammatory activation and malignant progression.

• Detailed identification of plasma proteins adsorbed on copolymer nanoparticles.

  Authors: Tommy Cedervall, Iseult Lynch, Martina Foy, Tord Berggård, Seamas C Donnelly, Gerard Cagney, Sara Linse, Kenneth A Dawson

  Angewandte Chemie (International ed. in English). 02/2007; 46(30):5754-6.

• Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction.

  Authors: Ramón Martos, John Baugh, Mark Ledwidge, Christina O'Loughlin, Carmel Conlon, Anil Patle, Seamas C Donnelly, Kenneth McDonald

  Circulation. 02/2007; 115(7):888-95.

  BACKGROUND: The pathophysiology of diastolic heart failure (DHF) is poorly understood. One potential explanation is an active fibrotic process that produces increased ventricular stiffness, whichBACKGROUND: The pathophysiology of diastolic heart failure (DHF) is poorly understood. One potential explanation is an active fibrotic process that produces increased ventricular stiffness, which compromises filling. The present study investigates collagen metabolism in hypertensive patients in different phases of diastolic function with and without proven DHF. METHODS AND RESULTS: We studied 86 hypertensive patients divided into groups according to the presence of DHF (32 with, 54 without) and phase of diastolic function (20 with normal function, 38 with impaired relaxation, 10 with pseudonormalization, and 16 with restrictive-like filling). Serum carboxy-terminal, amino-terminal, and carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, matrix metalloproteinases (MMPs; total MMP-1, active MMP-2, and MMP-9), and tissue inhibitor of MMPs levels were assayed by radioimmunoassay and ELISA. Doppler-echocardiographic assessment of diastolic filling was made with measurements of E/A ratio, E-wave deceleration time, and isovolumic relaxation time. Serum carboxy-terminal telopeptide of procollagen type I, carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 levels (P<0.001 for all, controlled for age and gender) were greater in patients with DHF than in those without. When we controlled for age and gender, levels of serum carboxy-terminal telopeptide of procollagen type I, tissue inhibitor of MMP-1, amino-terminal propeptide of procollagen type III (all P<0.001), carboxy-terminal telopeptide of procollagen type I (P=0.008), and MMP-2 (P=0.03) were greater in more severe phases of diastolic dysfunction. Within phases of diastolic dysfunction, serum carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 were elevated in those with DHF compared with those without DHF (all P<0.001). CONCLUSIONS: These data demonstrate serological evidence of an active fibrotic process in DHF, which is more marked in more severe diastolic dysfunction. This observation may help explain the pathophysiology of DHF and may suggest new avenues for diagnostic and therapeutic intervention.

• Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1.

  Authors: John A Baugh, Michael Gantier, Lili Li, Aileen Byrne, Avril Buckley, Seamas C Donnelly

  Biochemical and biophysical research communications. 10/2006; 347(4):895-903.

  Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However,Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.

• The SERPINE2 gene and chronic obstructive pulmonary disease.

  Authors: Sally Chappell, Leslie Daly, Kevin Morgan, Tamar Guetta-Baranes, Josep Roca, Roberto Rabinovich, Ann Millar, Seamas C Donnelly, Vera Keatings, William MacNee, Jan Stolk, Pieter S Hiemstra, Massimo Miniati, Simonetta Monti, Clare M O'Connor, Noor Kalsheker

  American journal of human genetics. 08/2006; 79(1):184-6; author reply 186-7.

• Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease.

  Authors: Sally Chappell, Leslie Daly, Kevin Morgan, Tamar Guetta-Baranes, Josep Roca, Roberto Rabinovich, Ann Millar, Seamas C Donnelly, Vera Keatings, William MacNee, Jan Stolk, Pieter Hiemstra, Massimo Miniati, Simonetta Monti, Clare M O'Connor, Noor Kalsheker

  Human mutation. 02/2006; 27(1):103-9.

  Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. While cigarette smoking is a major cause of COPD, only 15% of smokers develop the disease,Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. While cigarette smoking is a major cause of COPD, only 15% of smokers develop the disease, indicating major genetic influences. The most widely recognized candidate gene in COPD is SERPINA1, although it has been suggested that SERPINA3 may also play a role. To detect cryptic genetic variants that might contribute to disease, we identified 15 SNP haplotype tags from high-density SNP maps of the two genes and evaluated these SNPs in the largest case-control genetic study of COPD conducted so far. For SERPINA1, six newly identified haplotypes with a common backbone of five SNPs were found to increase the risk of disease by six- to 50-fold, the highest risk of COPD reported to date. In contrast, no haplotype associations for SERPINA3 were identified.

• Cystic fibrosis, disease severity, and a macrophage migration inhibitory factor polymorphism.

  Authors: Barry J Plant, Charles G Gallagher, Richard Bucala, John A Baugh, Sally Chappell, Linda Morgan, Clare M O'Connor, Kevin Morgan, Seamas C Donnelly

  American journal of respiratory and critical care medicine. 01/2006; 172(11):1412-5.

  RATIONALE: Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. It contributes toward an exaggerated gram-negative inflammatory response via its ability to induce Toll-likeRATIONALE: Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. It contributes toward an exaggerated gram-negative inflammatory response via its ability to induce Toll-like receptor-4 expression. Studies have shown that MIF knockout mice have less aggressive Pseudomonas infection (compared with wild-type). OBJECTIVES: To assess whether a novel functional MIF polymorphism was associated with clinical prognosis in a patient cohort with chronic gram-negative infection, namely cystic fibrosis (CF). METHODS: Collected genomic DNA was analyzed via polymerase chain reaction amplification for the polymorphic region for the CATT repeat polymorphism. Individuals may have a 5-, 6-, 7-, or 8-CATT tetranucleotide repeat unit on each allele. The 5-CATT repeat allele exhibits the lowest MIF promoter activity. MEASUREMENTS AND MAIN RESULTS: Patients with stable CF (n = 167) and a matched control group (n = 166) were enrolled. In patients with CF, the MIF5(+) group had a decreased incidence of Pseudomonas aeruginosa colonization (odds ratio, 0.25; 95% confidence interval, 0.09-0.65; p = 0.004) and a significant reduction in the risk of pancreatic insufficiency (odds ratio, 0.27; 95% confidence interval, 0.07-1.0; p = 0.05). A trend toward milder disease activity in the MIF5(+) group was seen with all other parameters. CONCLUSIONS: The results support the concept of a regulatory role for MIF in CF.

• Macrophage migration inhibitory factor is associated with aneurysmal expansion.

  Authors: Jie-Hong Pan, Jes S Lindholt, Galina K Sukhova, John A Baugh, Eskild W Henneberg, Richard Bucala, Seamas C Donnelly, Peter Libby, Christine Metz, Guo-Ping Shi

  Journal of vascular surgery : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 04/2003; 37(3):628-35.

  BACKGROUND: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine released mainly from macrophages and activated lymphocytes. Both atherosclerosis and abdominal aortic aneurysmBACKGROUND: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine released mainly from macrophages and activated lymphocytes. Both atherosclerosis and abdominal aortic aneurysm (AAA) are inflammatory diseases tightly linked to the function of these cells. The correlation and contribution of MIF to these human diseases remain unknown, although a recent rabbit study showed expression of this cytokine in atherosclerotic lesions. MATERIAL AND METHODS: MIF immunohistochemistry was performed on tissue sections from five normal aortas, seven atherosclerotic carotids, and six AAAs. A group of 112 men with small AAAs (defined as 3 to 5 cm) was recruited at the time of diagnosis, had serum samples taken, and was followed annually for 1 to 5 years (mean, 2.9 years) and referred for surgery if the AAA exceeded 5 cm in diameter. Of this study group, 98 had serum MIF measured with an enzyme-linked immunosorbent assay and 61 had detectable levels. RESULTS: In human atherosclerotic and aneurysmal lesions, MIF protein colocalized in macrophages, endothelial cells, and smooth muscle cells, but normal arteries had negligible MIF expression. Furthermore, serum-MIF levels correlated significantly with annual expansion rate (r = 0.28; P =.005), persisting after adjustment for initial AAA size, smoking habits, diastolic blood pressure, ankle blood pressure index, and age. After exclusion of 38 cases with MIF levels below the detection limit, initial AAA size was also significantly correlated with the MIF levels (r = 0.42; P =.001), persisting after adjustment for similar confounders, and the correlation coefficient with expansion rate increased to 0.42 (P =.001). CONCLUSION: Highly expressed MIF in macrophages, endothelial cells, and smooth muscle cells in lesions from atherosclerosis and AAA and significant association between serum MIF level and AAA initial size and AAA expansion rate in a group of patients with AAA suggest a potential involvement of this proinflammatory cytokine in the pathogenesis of these cardiovascular diseases.

• Imbalance in the expression of CXC chemokines correlates with bronchoalveolar lavage fluid angiogenic activity and procollagen levels in acute respiratory distress syndrome.

  Authors: Michael P Keane, Seamas C Donnelly, John A Belperio, Richard B Goodman, Maria Dy, Marie D Burdick, Michael C Fishbein, Robert M Strieter

  Journal of immunology (Baltimore, Md. : 1950). 01/2003; 169(11):6515-21.

  Diffuse alveolar damage is the histopathological hallmark of acute respiratory distress syndrome (ARDS) and is a stereotypic response to a variety of etiologies. Moreover, a significant proportion ofDiffuse alveolar damage is the histopathological hallmark of acute respiratory distress syndrome (ARDS) and is a stereotypic response to a variety of etiologies. Moreover, a significant proportion of ARDS survivors have residual pulmonary fibrosis and compromised pulmonary function. This suggests that the pathogenesis of diffuse alveolar damage that ultimately leads to the chronic fibrosis of ARDS has features of dysregulated repair exemplified by exaggerated intra-alveolar angiogenesis and fibrogenesis (i.e., fibroproliferation and deposition of extracellular matrix), leading to progressive alveolar fibrosis and impaired lung function. We obtained bronchoalveolar lavage fluid (BALF) from patients with ARDS or ventilated control patients and assessed CXC chemokine levels by ELISA. We found an imbalance in the expression of ELR(+) as compared with ELR(-) CXC chemokines from BALF of patients with ARDS as compared with controls. This imbalance correlated with angiogenic activity as assessed by the corneal micropocket assay. Furthermore, these levels correlated with both procollagen I and procollagen III levels in BALF. In contrast, while BALF levels of vascular endothelial growth factor were elevated, vascular endothelial growth factor did not appear to be significantly contributing to the angiogenic activity. These findings suggest that CXC chemokines have an important role in the fibroproliferative phase of ARDS via the regulation of angiogenesis.

• Anti-interleukin-8 autoantibodies in patients at risk for acute respiratory distress syndrome.

  Authors: Anna Kurdowska, James M Noble, Ian S Grant, Colin R Robertson, Christopher Haslett, Seamas C. Donnelly

  Critical care medicine. 10/2002; 30(10):2335-7.

  OBJECTIVE: To test the hypothesis that elevated concentrations of interleukin-8 associated with anti-interleukin-8 autoantibodies (anti-interleukin-8:interleukin-8 complexes) are found in patients atOBJECTIVE: To test the hypothesis that elevated concentrations of interleukin-8 associated with anti-interleukin-8 autoantibodies (anti-interleukin-8:interleukin-8 complexes) are found in patients at risk for acute respiratory distress syndrome who developed the disease. DESIGN: Measurement of anti-interleukin-8:interleukin-8 complex concentrations in previously collected bronchoalveolar lavage fluids. These fluids were obtained from patients at risk for acute respiratory distress syndrome who subsequently either recovered or developed acute respiratory distress syndrome. PATIENTS: A unique population of patients at risk for acute respiratory distress syndrome was studied. There were 26 patients at risk for acute respiratory distress syndrome who were divided into three groups. Group I patients had high interleukin-8 concentrations and developed acute respiratory distress syndrome, group II had high interleukin-8 concentrations and did not develop acute respiratory distress syndrome, and group III had low interleukin-8 concentrations and did not develop acute respiratory distress syndrome. These patients were selected to test the hypothesis that presence of elevated concentrations of anti-interleukin-8:interleukin-8 complexes differentiates patients at risk for acute respiratory distress syndrome who developed acute respiratory distress syndrome from patients who did not. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid concentrations of interleukin-8 associated with the anti-interleukin-8 autoantibodies were significantly different between groups (p <.03). The amount of interleukin-8 bound to the anti-interleukin-8 autoantibody was higher in group I than in group II and group III. CONCLUSIONS: Bronchoalveolar lavage fluid concentration of anti-interleukin-8:interleukin-8 complexes may serve as a marker of disease progression in patients at risk for acute respiratory distress syndrome.