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James H. Shelhamer - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor alpha stimulation of human clara cell Secretory Protein production by human airway epithelial cells
Annals of the New York Academy of Sciences, 2006Co-Authors: M J Cowan, Xiulie Huang, James H. ShelhamerAbstract:: Clara cell Secretory Protein (CCSP) or uteroglobin/CC10 is a product of epithelial cells in a variety of organs including the lung. CCSP has anti-inflammatory properties and may act as an inhibitor of Secretory phospholipase A2's. Tumor necrosis factor alpha (TNF-alpha) is capable of inducing the expression of gene products including a variety of cytokines and chemokines in the airway epithelium that may upregulate the airway inflammatory response. Therefore, it was of interest to determine whether this proinflammatory cytokine might also induce the production of a counterregulatory Protein such as CCSP, which might modulate the inflammatory response in the airway. Normal human tracheobronchial epithelial cells in primary culture and a human bronchial epithelial cell line (BEAS-2B) were studied. CCSP mRNA levels in BEAS-2B cells were detected by ribonuclease protection assay. CCSP mRNA levels increased in response to TNF-alpha (20 ng/mL) stimulation after 8-36 h, with the peak increase at 18 h. Immunoblotting of CCSP released from BEAS-2B cells into the culture media demonstrated that TNF-alpha induced the synthesis and secretion of CCSP over 8 to 18 h. Similarly, TNF stimulated the release of CCSP from human tracheobronchial epithelial cells in primary culture at 8 and 18 h. The CCSP reporter gene including 801 bases 5' of the transcription start site did not increase transcriptional activity in response to TNF-alpha stimulation. A CCSP mRNA half-life assay indicated that TNF-alpha induced increases in CCSP mRNA at least in part at a posttranscriptional level. Therefore, TNF-alpha induces airway epithelial cell expression of human CCSP and may modulate airway inflammatory responses in this manner.
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tumor necrosis factor α stimulates human clara cell Secretory Protein production by human airway epithelial cells
American Journal of Respiratory Cell and Molecular Biology, 1998Co-Authors: Stewart J Levine, M J Cowan, Carolea Logun, James H. ShelhamerAbstract:Clara cell Secretory Protein (CCSP), or CC10, is an inhibitor of Secretory phospholipase A2 which may be produced by phagocytic cells and by a variety of other cells in the airway. Tumor necrosis factor-α (TNF-α) is capable of activating phospholipases and inducing the expression of a variety of genes in the airway epithelium which may modulate the airway inflammatory response. Therefore, it was of interest to determine whether this proinflammatory cytokine could induce the production of a counterregulatory Protein such as CCSP which might modulate the production of eicosanoid mediators in the airway. Using a human bronchial epithelial cell line (BEAS-2B), CCSP messenger RNA (mRNA) levels were detected by ribonuclease protection assay. TNF treatment of these cells increased CCSP mRNA levels in a time- and dose-dependent manner. The CCSP mRNA level increased in response to TNF-α (20 ng/ml) stimulation after 8 to 36 h with the peak increase at 18 h. Immunoblotting of CCSP Protein released into the culture m...
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interferon γ stimulates human clara cell Secretory Protein production by human airway epithelial cells
American Journal of Physiology-lung Cellular and Molecular Physiology, 1998Co-Authors: Xianglan Yao, M J Cowan, Carolea Logun, Tetsuo Ikezono, C W Angus, James H. ShelhamerAbstract:Clara cell Secretory Protein (CCSP) is an inhibitor of Secretory phospholipase A2. It is produced by airway epithelial cells and is present in airway secretions. Because interferon (IFN)-γ can indu...
Barry R Stripp - One of the best experts on this subject based on the ideXlab platform.
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protective role for club cell Secretory Protein 16 cc16 in the development of copd
European Respiratory Journal, 2015Co-Authors: Maria E Lauchocontreras, Kushagra Gupta, Katherine L Taylor, Emer Kelly, Miguel Divo, Naveed Ashfaq, Victor Pintoplata, Francesca Polverino, Hans Petersen, Barry R StrippAbstract:Club cell Secretory Protein-16 (CC16) is the major secreted product of airway club cells, but its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD murine model. Airway CC16 expression was measured in COPD patients, smokers without COPD and non-smokers. We exposed wildtype (WT) and CC16(-/-)mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway mucin 5AC (MUC5AC) expression, small airway remodelling and pulmonary function. Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16(-/-) mice had greater CS-induced emphysema, airway remodelling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NF-κB) activation in CC16(-/-) lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. CC16 protects lungs from CS-induced injury by reducing lung NF-κB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD.
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elevation of susceptibility to ozone induced acute tracheobronchial injury in transgenic mice deficient in clara cell Secretory Protein
Toxicology and Applied Pharmacology, 2006Co-Authors: Gregory W Mango, Susan D Reynolds, G E Hatch, Viviana J Wong, Elina Toskala, Brian K. Tarkington, Barry R StrippAbstract:Increases in Clara cell abundance or cellular expression of Clara cell Secretory Protein (CCSP) may cause increased tolerance of the lung to acute oxidant injury by repeated exposure to ozone (O{sub 3}). This study defines how disruption of the gene for CCSP synthesis affects the susceptibility of tracheobronchial epithelium to acute oxidant injury. Mice homozygous for a null allele of the CCSP gene (CCSP-/-) and wild type (CCSP+/+) littermates were exposed to ozone (0.2 ppm, 8 h; 1 ppm, 8 h) or filtered air. Injury was evaluated by light and scanning electron microscopy, and the abundance of necrotic, ciliated, and nonciliated cells was estimated by morphometry. Proximal and midlevel intrapulmonary airways and terminal bronchioles were evaluated. There was no difference in airway epithelial composition between CCSP+/+ and CCSP-/- mice exposed to filtered air, and exposure to 0.2 ppm ozone caused little injury to the epithelium of both CCSP+/+ and CCSP-/- mice. After exposure to 1.0 ppm ozone, CCSP-/- mice suffered from a greater degree of epithelial injury throughout the airways compared to CCSP+/+ mice. CCSP-/- mice had both ciliated and nonciliated cell injury. Furthermore, lack of CCSP was associated with a shift in airway injury to include proximal airway generations.more » Therefore, we conclude that CCSP modulates the susceptibility of the epithelium to oxidant-induced injury. Whether this is due to the presence of CCSP on the acellular lining layer surface and/or its intracellular distribution in the Secretory cell population needs to be defined.« less
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clara cell Secretory Protein deficiency alters clara cell Secretory apparatus and the Protein composition of airway lining fluid
American Journal of Respiratory Cell and Molecular Biology, 2002Co-Authors: Barry R Stripp, Susan D Reynolds, Johan Lund, John H T Power, John T Coppens, Virginia Wong, Paul R ReynoldsAbstract:Clara cells represent the predominant Secretory cell within distal conducting airways of mammals and exhibit functional alterations with chronic lung disease. We previously demonstrated that Clara cell Secretory Protein (CCSP) deficiency results in enhanced susceptibility to environmental agents. The present study was undertaken to define changes in Clara cell Secretory function associated with CCSP deficiency in knockout mice. Comparative morphometry of Clara cell ultrastructure revealed dramatic alterations in Secretory apparatus between wild-type (WT) and CCSP knockout (CCSP−/−) mice. Secretory granules, which occupy greater than 2% of Clara cell cytoplasmic volume in WT mice, were completely absent among Clara cells of CCSP−/− mice. Moreover, Clara cells of CCSP−/− mice exhibited a > 95% reduction in rough endoplasmic reticulum and alterations to Golgi apparatus, relative to WT controls. Ultrastructural perturbations to Clara cells were associated with altered Protein composition of airway lining flui...
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clara cell Secretory Protein expressing cells of the airway neuroepithelial body microenvironment include a label retaining subset and are critical for epithelial renewal after progenitor cell depletion
American Journal of Respiratory Cell and Molecular Biology, 2001Co-Authors: Kyung U Hong, Susan D Reynolds, Adam Giangreco, Cheryl M Hurley, Barry R StrippAbstract:Stem cells with potential to contribute to the re-establishment of the normal bronchiolar epithelium have not been definitively demonstrated. We previously established that neuroepithelial bodies (NEBs) sequester regenerative cells that contribute to bronchiolar regeneration after selective chemical depletion of Clara cells, a major progenitor cell population. Two candidate stem cells were identified on the basis of proliferative potential after chemical ablation: a pollutant-resistant subpopulation of Clara cells that retain their expression of Clara cell Secretory Protein (CCSP) (variant CCSP-expressing [CE] cells or vCE cells) and calcitonin gene-related peptide (CGRP)–expressing pulmonary neuroendocrine cells (PNECs). In the present study, two populations of label-retaining cells were identified within the NEB: CGRP-expressing cells and a subpopulation of CE cells. To investigate contributions made by CE and CGRP-expressing cells to epithelial renewal, CE cells were ablated through acute administratio...
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normal function and lack of fibronectin accumulation in kidneys of clara cell Secretory Protein uteroglobin deficient mice
American Journal of Kidney Diseases, 1999Co-Authors: Susan D Reynolds, Johan Lund, Gregory W Mango, Robert Gelein, Ingermargrethe Boe, Barry R StrippAbstract:Clara cell Secretory Protein (CCSP), also known as uteroglobin (Ug), is a 16-kDa homodimeric Protein of unknown function. Within rodent species, CCSP is expressed predominantly by nonciliated Clara cells that line conducting airways of the lung. To investigate in vivo functions for CCSP, we established mice homozygous for a null allele of the CCSP gene (CCSP-/-). We previously showed no overt phenotypic consequences associated with CCSP deficiency when CCSP-/- mice are maintained in the absence of environmental stress. However, CCSP-/- mice show an oxidant-sensitive phenotype that cannot be attributed to alterations in the inflammatory response when challenged by inhaled oxidant gases. The current study was undertaken to determine whether CCSP deficiency results in pathological changes to the kidney. This study was prompted by the recent description of severe systemic disease and kidney fibrosis/dysfunction in an independent line of CCSP-deficient mice, termed Ug-/- (Zhang et al, Science 276:1408-1412, 1997). CCSP-/- mice show normal growth and reproductive performance when maintained in two independent genetic backgrounds, inbred 129 and congenic C57BL/6. Strain 129 CCSP-/- mice have normal kidney function, as assessed by urinary glucose, lactate dehydrogenase, and glomerular filtration rate; they show no kidney fibrosis or abnormalities in fibronectin accumulation and no histological abnormalities in proximal convoluted tubules or glomeruli at either light or electron microscopic levels. CCSP deficiency is associated with mild Proteinurea involving a modest increase in mouse major urinary Protein-1. We conclude that CCSP (Ug) deficiency, per se, is not the cause of severe renal pathology and systemic disease reported for Ug-/- mice.
M J Cowan - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor alpha stimulation of human clara cell Secretory Protein production by human airway epithelial cells
Annals of the New York Academy of Sciences, 2006Co-Authors: M J Cowan, Xiulie Huang, James H. ShelhamerAbstract:: Clara cell Secretory Protein (CCSP) or uteroglobin/CC10 is a product of epithelial cells in a variety of organs including the lung. CCSP has anti-inflammatory properties and may act as an inhibitor of Secretory phospholipase A2's. Tumor necrosis factor alpha (TNF-alpha) is capable of inducing the expression of gene products including a variety of cytokines and chemokines in the airway epithelium that may upregulate the airway inflammatory response. Therefore, it was of interest to determine whether this proinflammatory cytokine might also induce the production of a counterregulatory Protein such as CCSP, which might modulate the inflammatory response in the airway. Normal human tracheobronchial epithelial cells in primary culture and a human bronchial epithelial cell line (BEAS-2B) were studied. CCSP mRNA levels in BEAS-2B cells were detected by ribonuclease protection assay. CCSP mRNA levels increased in response to TNF-alpha (20 ng/mL) stimulation after 8-36 h, with the peak increase at 18 h. Immunoblotting of CCSP released from BEAS-2B cells into the culture media demonstrated that TNF-alpha induced the synthesis and secretion of CCSP over 8 to 18 h. Similarly, TNF stimulated the release of CCSP from human tracheobronchial epithelial cells in primary culture at 8 and 18 h. The CCSP reporter gene including 801 bases 5' of the transcription start site did not increase transcriptional activity in response to TNF-alpha stimulation. A CCSP mRNA half-life assay indicated that TNF-alpha induced increases in CCSP mRNA at least in part at a posttranscriptional level. Therefore, TNF-alpha induces airway epithelial cell expression of human CCSP and may modulate airway inflammatory responses in this manner.
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tumor necrosis factor α stimulates human clara cell Secretory Protein production by human airway epithelial cells
American Journal of Respiratory Cell and Molecular Biology, 1998Co-Authors: Stewart J Levine, M J Cowan, Carolea Logun, James H. ShelhamerAbstract:Clara cell Secretory Protein (CCSP), or CC10, is an inhibitor of Secretory phospholipase A2 which may be produced by phagocytic cells and by a variety of other cells in the airway. Tumor necrosis factor-α (TNF-α) is capable of activating phospholipases and inducing the expression of a variety of genes in the airway epithelium which may modulate the airway inflammatory response. Therefore, it was of interest to determine whether this proinflammatory cytokine could induce the production of a counterregulatory Protein such as CCSP which might modulate the production of eicosanoid mediators in the airway. Using a human bronchial epithelial cell line (BEAS-2B), CCSP messenger RNA (mRNA) levels were detected by ribonuclease protection assay. TNF treatment of these cells increased CCSP mRNA levels in a time- and dose-dependent manner. The CCSP mRNA level increased in response to TNF-α (20 ng/ml) stimulation after 8 to 36 h with the peak increase at 18 h. Immunoblotting of CCSP Protein released into the culture m...
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interferon γ stimulates human clara cell Secretory Protein production by human airway epithelial cells
American Journal of Physiology-lung Cellular and Molecular Physiology, 1998Co-Authors: Xianglan Yao, M J Cowan, Carolea Logun, Tetsuo Ikezono, C W Angus, James H. ShelhamerAbstract:Clara cell Secretory Protein (CCSP) is an inhibitor of Secretory phospholipase A2. It is produced by airway epithelial cells and is present in airway secretions. Because interferon (IFN)-γ can indu...
Jeffrey A Whitsett - One of the best experts on this subject based on the ideXlab platform.
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expression of thyroid transcription factor 1 surfactant Proteins type i cell associated antigen and clara cell Secretory Protein in pulmonary hypoplasia
Pediatric and Developmental Pathology, 2001Co-Authors: Hong Zhou, Jeffrey A Whitsett, Raffaella A Morotti, Sherri A Profitt, Claire Langston, Susan E Wert, Alba M GrecoAbstract:Pulmonary hypoplasia (PH) is a developmental abnormality characterized by diminished distal lung parenchyma. Recent studies have demonstrated that thyroid transcription factor 1 (TTF-1), a member of NK×2 family of homeodomain transcription factors, plays an important role in lung organogenesis and lung epithelial gene expression. In order to evaluate whether abnormal expression of TTF-1 contributes to the pathophysiology of PH, we studied the expression of TTF-1, as well as that of the surfactant Proteins (SPs), Clara cell Secretory Protein (CCSP), and type I cell–associated antigen (T1 cell-Ag), in PH. Immunolocalization patterns of these Proteins were evaluated in 15 cases of PH with different associated diseases and compared with those of 14 matched controls. Our study demonstrated that the concentration gradient of TTF-1 along the proximal–distal axis in normal fetal lung is disrupted in PH after 24 weeks gestational age, while the expression of the SPs, CCSP, and T1 cell-Ag seemed to be preserved. We conclude that a normal TTF-1 expression pattern might be crucial in the control of distal lung development. Failure to switch off expression of TTF-1 in PH of more than 24 weeks gestational age may be a final common pathway leading to PH associated with the disease processes investigated in this study.
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clara cell Secretory Protein decreases lung inflammation after acute virus infection
American Journal of Physiology-lung Cellular and Molecular Physiology, 1998Co-Authors: Kevin S Harrod, Amber D Mounday, Barry R Stripp, Jeffrey A WhitsettAbstract:Clara cell Secretory Protein (CCSP) is an abundant 10-kDa polypeptide synthesized and secreted primarily by nonciliated bronchiolar epithelial cells in the mammalian lung. To determine the potentia...
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clara cell Secretory Protein a determinant of pcb bioaccumulation in mammals
American Journal of Physiology-lung Cellular and Molecular Physiology, 1996Co-Authors: Barry R Stripp, Magnus Nord, Gregory W Mango, K C Doyen, J. Lund, Carl J Johnston, Kjell Hultenby, Jeffrey A WhitsettAbstract:Clara cell Secretory Protein (CCSP) is a product of nonciliated cells of the conducting airway epithelium. The normal physiological function of CCSP is unknown. However, the ability of CCSP to bind...
Arnaud Bourdin - One of the best experts on this subject based on the ideXlab platform.
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club cell Secretory Protein serum concentration is a surrogate marker of small airway involvement in asthmatic patients
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Sebastien Bommart, Anne Sophie Gamez, Lucie Knabe, Gregory Marin, Catherine Devautour, Aurélie Petit, Nicolas Molinari, Isabelle Vachier, Pascal Chanez, Arnaud BourdinAbstract:Poor asthma control and recurrent exacerbations have been shown to be a phenotypic counterpart of asthma with predominantly small-airway involvement.1 Biomarkers are not always accurate in asthmatic patients, especially in serum, because compartmentalization can occur between the blood and airways. Blood eosinophil counts do not represent an overall view of airway inflammation, and exhaled nitric oxide measurements at different flow rates (fraction of exhaled nitric oxide [Feno] and alveolar nitric oxide [Calvno]) have been developed and validated to reflect more accurately proximal and distal airway inflammation.2 Club cell Secretory Protein (CCSP) serum concentration has been shown to be associated with chronic obstructive pulmonary disease, bronchiolitis obliterans syndrome, and sarcoidosis, which are all predominantly diseases involving the small airways. Ranges of CCSP concentrations in healthy subjects, reproducibility, and relationships between serum and airway levels are known and can be used as potential surrogate markers. Our aim was to assess small-airway disease in asthmatic patients and to find a related biomarker. We used a dynamic assessment of gas trapping using computed tomographic (CT) imaging of the chest during methacholine challenge as a marker of small-airway disease.
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supplementing defect in club cell Secretory Protein attenuates airway inflammation in copd
Chest, 2015Co-Authors: Anne Sophie Gamez, Lucie Knabe, Aurélie Petit, Delphine Gras, Nicolas Molinari, Isabelle Vachier, Pascal Chanez, Arnaud BourdinAbstract:BACKGROUND Club cell Secretory Protein (CCSP) is a protective biomarker associated with annual decline in lung function. COPD progression results from an imbalance between injury and repair initially triggered by cigarette smoking. OBJECTIVE We investigated the effect of CCSP as a therapeutic strategy to restore the balance between injury and repair in COPD simultaneously, validating an ex vivo air-liquid interface (ALI) culture of human bronchial epithelial cells. METHODS Endobronchial biopsy specimens (EBBs) were obtained from 13 patients with COPD, eight smokers, and eight control subjects. Morphometric analysis of the initial EBBs was performed. ALI cultures derived from the same EBBs were exposed to cigarette smoke extract (CSE) with or without exogenous recombinant human CCSP (rhCCSP) supplementation. CCSP and IL-8 concentrations were assessed at steady state and after CSE exposure. RESULTS Morphometric analysis of the initial EBBs showed increased cell density but decreased immunostaining of CCSP+ cells in EBBs of patients with COPD (P = .03 vs control subjects). At steady state, lower CCSP (P = .04) and higher IL-8 levels (P CONCLUSIONS In vitro, rhCCSP exogenous supplementation can reverse CSE-induced IL-8 release in biopsy specimens from patients with COPD, indicating a potential use of this strategy in vivo.
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supplementing defect in club cell Secretory Protein attenuates airway inflammation in copd
Chest, 2015Co-Authors: Anne Sophie Gamez, Lucie Knabe, Aurélie Petit, Delphine Gras, Nicolas Molinari, Isabelle Vachier, Pascal Chanez, Arnaud BourdinAbstract:BACKGROUND Club cell Secretory Protein (CCSP) is a protective biomarker associated with annual decline in lung function. COPD progression results from an imbalance between injury and repair initially triggered by cigarette smoking. OBJECTIVE We investigated the effect of CCSP as a therapeutic strategy to restore the balance between injury and repair in COPD simultaneously, validating an ex vivo air-liquid interface (ALI) culture of human bronchial epithelial cells. METHODS Endobronchial biopsy specimens (EBBs) were obtained from 13 patients with COPD, eight smokers, and eight control subjects. Morphometric analysis of the initial EBBs was performed. ALI cultures derived from the same EBBs were exposed to cigarette smoke extract (CSE) with or without exogenous recombinant human CCSP (rhCCSP) supplementation. CCSP and IL-8 concentrations were assessed at steady state and after CSE exposure. RESULTS Morphometric analysis of the initial EBBs showed increased cell density but decreased immunostaining of CCSP+ cells in EBBs of patients with COPD (P = .03 vs control subjects). At steady state, lower CCSP (P = .04) and higher IL-8 levels (P < .0001) were found in COPD ALI epithelium. Exogenous rhCCSP supplementation dampened CSE-induced IL-8-release in patients with COPD and returned to levels similar to those of smokers and control subjects (P = .0001). A negative correlation was found between IL-8-release in ALI and CCSP+ cell density in initial biopsy specimens (P = .0073). CONCLUSIONS In vitro, rhCCSP exogenous supplementation can reverse CSE-induced IL-8 release in biopsy specimens from patients with COPD, indicating a potential use of this strategy in vivo.
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donor clara cell Secretory Protein polymorphism is a risk factor for bronchiolitis obliterans syndrome after lung transplantation
Transplantation, 2012Co-Authors: Arnaud Bourdin, Pascal Chanez, Nicole A Mifsud, Brice Chanez, Catriona Mclean, Greg Snell, Tom KotsimbosAbstract:Background. We hypothesized that a reduced potential for bronchiolar stem-cell (Clara cell)Yrelated repair in thesetting ofan ever-present risk of small airway injury would increase the risk of bronchiolitis obliterans syndrome (BOS).Method. CCSP A38G gene polymorphism was assessed in both lung donors and recipients in a longitudinal studycohort of 63 consecutive lung transplant recipients (LTR) with a median follow-up of 493 days (range, 26Y894). Claracell Secretory Protein (CCSP) and interleukin 8 levels were assessed in the bronchoalveolar lavage and plasma at 1, 3, 6,and 12 months after transplantation. CCSP-positive cells were assessed in transbronchial biopsies at 1 and 3 months.Results. Of the 63 LTR, there were 5 early deaths (e90 days, 8% [95% confidence interval, 4%Y21%]), and 20 developedBOS (32%, [95% confidence interval, 21%Y45%]). Donor but not recipient CCSP A38G polymorphism was associatedwith more risk of BOS (relative risk, 8.6 [2.2Y33.5], PG0.0001) and decreased overall survival (log-rank test, P=0.011).Bronchoalveolar lavage CCSP and CCSP/interleukin 8 levels were low and decreasing early after transplantation in LTRwho developed BOS (P=0.015). CCSP+ve cells in transbronchial biopsies increased at 3 months only in LTR whoremained free of BOS (P=0.003).Conclusion. Donor CCSP A38G polymorphism is associated with decreased CCSP levels early after lung transplan-tation and poor long-term outcomes.Keywords: Clara cells, Obliterative bronchiolitis, Lung transplantation, Polymorphism.(Transplantation 2012;94: 00Y00)
