Am. J. Respir. Crit. Care Med., Volume 164, Number 12, December 2001, 2220-2228

Interleukin-4 and Interleukin-5 Gene Expression and Inflammation in the Mucus-secreting Glands and Subepithelial Tissue of Smokers with Chronic Bronchitis
Lack of Relationship with CD8⁺ Cells

JIE ZHU, SWATI MAJUMDAR, YUSHENG QIU, TAREQ ANSARI, ALESSANDRO OLIVA, JOHAN C. KIPS, ROMAIN A. PAUWELS, VIRGINIA DE ROSE, and PETER K. JEFFERY

Department of Gene Therapy, Imperial College School of Medicine, London, United Kingdom; Department of Clinical and Biological Sciences, University of Torino, Turin, Italy; and Department of Pathology, University Hospital, Ghent, Belgium

We wished to determine if the inflammatory cells surrounding the airway mucus-secreting glands in chronic bronchitis (CB) were associated with interleukin (IL)-4 and IL-5 mRNA expression and whether the CD8 T cell population expressed these cytokines. Digoxigenin-labeled IL-4 and IL-5 antisense RNA probes were used to detect gene expression in 11 asymptomic smokers (AS), 11 smokers with CB alone with normal lung function, and 10 smokers with chronic bronchitis and coexisting chronic obstructive pulmonary disease (CB+COPD; FEV₁% of predicted of 43-77% and FEV₁/ FVC of 51-68%). There were approximately three times as many IL-4 than IL-5 mRNA⁺ cells. The highest number of IL-4 mRNA⁺ cells were in the submucosal glands of the CB group with normal lung function (216/mm²), significantly higher than the values in either the AS (63/mm²) or the CB+COPD (87/mm²) groups, respectively (p < 0.01). There were similar group differences when the total numbers of inflammatory cells were compared. Accordingly, there was a positive correlation between the number of IL-4 mRNA⁺ cells and the total number of inflammatory cells in both the subepithelium and glandular compartments (r = 0.60; p = 0.01 and r = 0.70; p = 0.02, respectively). There were no significant associations between the numbers of CD8⁺ and IL-4 or IL-5 mRNA⁺ cells. Of 1328 IL-4⁺ and 1404 CD8⁺ cells counted none was double labeled. Of 727 IL-5⁺ and 1569 CD8⁺ cells, none was double labeled. In contrast, as a positive control, 34% of tumor necrosis factor (TNF)-⁺ cells were also CD8⁺ and 15% of CD8⁺ cells were TNF- positive. Thus, cells other than the CD8⁺ phenotype produce IL-4 and IL-5 in CB. We conclude that there is increased inflammation and IL-4 gene expression in the mucus-secreting glands and the airway mucosa of smokers with bronchitis: both are lower in those with CB and coexisting COPD suggesting that airway inflammation in CB is reduced when airway obstruction develops.

This article has been cited by other articles:

				D. Mehra, D. I. Sternberg, Y. Jia, S. Canfield, V. Lemaitre, T. Nkyimbeng, J. Wilder, J. Sonett, and J. D'Armiento Altered lymphocyte trafficking and diminished airway reactivity in transgenic mice expressing human MMP-9 in a mouse model of asthma Am J Physiol Lung Cell Mol Physiol, February 1, 2010; 298(2): L189 - L196. [Abstract] [Full Text] [PDF]

				B. R. Celli and P. J. Barnes Exacerbations of chronic obstructive pulmonary disease Eur. Respir. J., June 1, 2007; 29(6): 1224 - 1238. [Abstract] [Full Text] [PDF]

				J. Zhu, Y. Qiu, M. Valobra, S. Qiu, S. Majumdar, D. Matin, V. De Rose, and P. K. Jeffery Plasma Cells and IL-4 in Chronic Bronchitis and Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 2007; 175(11): 1125 - 1133. [Abstract] [Full Text] [PDF]

				F. Guddo, A. M. Vignola, M. Saetta, S. Baraldo, L. Siena, E. Balestro, R. Zuin, A. Papi, P. Maestrelli, L. M. Fabbri, et al. Upregulation of basic fibroblast growth factor in smokers with chronic bronchitis Eur. Respir. J., May 1, 2006; 27(5): 957 - 963. [Abstract] [Full Text] [PDF]

				C. Bergeron and L.-P. Boulet Structural changes in airway diseases: characteristics, mechanisms, consequences, and pharmacologic modulation. Chest, April 1, 2006; 129(4): 1068 - 1087. [Abstract] [Full Text] [PDF]

				E. Gamble, Y. Qiu, D. Wang, J. Zhu, A. M. Vignola{dagger}, C. Kroegel, F. Morell, T. T. Hansel, I. D. Pavord, K. F. Rabe, et al. Variability of bronchial inflammation in chronic obstructive pulmonary disease: implications for study design Eur. Respir. J., February 1, 2006; 27(2): 293 - 299. [Abstract] [Full Text] [PDF]

				W. MacNee Pathogenesis of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 258 - 266. [Abstract] [Full Text] [PDF]

				E. F. M. Wouters Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 26 - 33. [Abstract] [Full Text] [PDF]

				P. K. Jeffery Remodeling and Inflammation of Bronchi in Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2004; 1(3): 176 - 183. [Abstract] [Full Text] [PDF]

				S. N. Georas Inhaled Glucocorticoids, Lymphocytes, and Dendritic Cells in Asthma and Obstructive Lung Diseases Proceedings of the ATS, November 1, 2004; 1(3): 215 - 221. [Abstract] [Full Text] [PDF]

				E. Gamble, W. Burns, J. Zhu, T. Ansari, V. De Rose, J. Kips, N.C. Barnes, and P.K. Jeffery Variation of CD8+ T-lymphocytes around the bronchial internal perimeter in chronic bronchitis Eur. Respir. J., December 1, 2003; 22(6): 992 - 995. [Abstract] [Full Text] [PDF]

				P. Panzner, J.-J. Lafitte, A. Tsicopoulos, Q. Hamid, and M. K. Tulic Marked Up-regulation of T Lymphocytes and Expression of Interleukin-9 in Bronchial Biopsies From Patients With Chronic Bronchitis With Obstruction Chest, November 1, 2003; 124(5): 1909 - 1915. [Abstract] [Full Text] [PDF]

				E. Gamble, D. C. Grootendorst, C. E. Brightling, S. Troy, Y. Qiu, J. Zhu, D. Parker, D. Matin, S. Majumdar, A. M. Vignola, et al. Antiinflammatory Effects of the Phosphodiesterase-4 Inhibitor Cilomilast (Ariflo) in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2003; 168(8): 976 - 982. [Abstract] [Full Text] [PDF]

				D. Miotto, M.P. Ruggieri, P. Boschetto, G. Cavallesco, A. Papi, I. Bononi, C. Piola, B. Murer, L.M. Fabbri, and C.E. Mapp Interleukin-13 and -4 expression in the central airways of smokers with chronic bronchitis Eur. Respir. J., October 1, 2003; 22(4): 602 - 608. [Abstract] [Full Text] [PDF]

				P.J. Barnes, S.D. Shapiro, and R.A. Pauwels Chronic obstructive pulmonary disease: molecular and cellularmechanisms Eur. Respir. J., October 1, 2003; 22(4): 672 - 688. [Abstract] [Full Text] [PDF]

				P. Jeffery, S. Holgate, and S. Wenzel Methods for the Assessment of Endobronchial Biopsies in Clinical Research: Application to Studies of Pathogenesis and the Effects of Treatment Am. J. Respir. Crit. Care Med., September 15, 2003; 168(6): S1 - 17. [Full Text] [PDF]

				G. L. Snider Understanding Inflammation in Chronic Obstructive Pulmonary Disease: The Process Begins Am. J. Respir. Crit. Care Med., April 15, 2003; 167(8): 1045 - 1046. [Full Text] [PDF]

				R. E. Walter, A. Beiser, R. J. Givelber, G. T. O'Connor, and D. J. Gottlieb Association between Glycemic State and Lung Function: The Framingham Heart Study Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 911 - 916. [Abstract] [Full Text] [PDF]

				J. Zhu, I. Kilty, H. Granger, E. Gamble, Y. S. Qiu, K. Hattotuwa, W. Elston, W. L. Liu, A. Oliva, R. A. Pauwels, et al. Gene Expression and Immunolocalization of 15-Lipoxygenase Isozymes in the Airway Mucosa of Smokers with Chronic Bronchitis Am. J. Respir. Cell Mol. Biol., December 1, 2002; 27(6): 666 - 677. [Abstract] [Full Text] [PDF]

				M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]