Am. J. Respir. Crit. Care Med., Volume 165, Number 8, April 2002, 1132-1136

Increased Expression of the Human Ca²⁺-activated Cl Channel 1 (CaCC1) Gene in the Asthmatic Airway

Makoto Hoshino, Shigeru Morita, Hiroki Iwashita, Yoji Sagiya, Toshimi Nagi, Atsushi Nakanishi, Yasuko Ashida, Osamu Nishimura, Yukio Fujisawa, and Masahiko Fujino

Second Department of Internal Medicine, Toho University School of Medicine, Tokyo, and Discovery Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Ibaraki, Japan

Mucus overproduction is a clinical feature of asthma. Ca²⁺-activated Cl channel 1 (CaCC1) has been identified as a protein that is expressed in intestinal epithelia and that plays an important role in fluid and electrolyte transport. Recently, its mouse counterpart, gob-5, was identified as a key molecule in the induction of murine asthma through mucus overproduction. To elucidate the relationship of CaCC1 to human asthma, we examined CaCC1 expression using real-time quantitative polymerase chain reaction analysis in bronchial tissues from patients with asthma and normal control subjects. The expression of CaCC1 was significantly upregulated in patients with bronchial asthma compared with control subjects. In situ hybridization and immunohistochemical analysis demonstrated that CaCC1 is located in the bronchial epithelium, especially in mucus-producing goblet cells. In vitro transfection of a CaCC1 expression vector into the human mucoepidermoid cell line, NCI-H292, increased mucus production and induced the MUC5AC gene. These results suggest that CaCC1 plays a direct role in mucus production and differentiation in goblet cells and may contribute to the pathogenesis of asthma through its mucus-inducing activity.

This article has been cited by other articles:

				M. K. Bothe, J. Braun, L. Mundhenk, and A. D. Gruber Murine mCLCA6 Is an Integral Apical Membrane Protein of Non-goblet Cell Enterocytes and Co-localizes With the Cystic Fibrosis Transmembrane Conductance Regulator J. Histochem. Cytochem., May 1, 2008; 56(5): 495 - 509. [Abstract] [Full Text] [PDF]

				F. Range, L. Mundhenk, and A. D. Gruber A Soluble Secreted Glycoprotein (eCLCA1) is Overexpressed Due to Goblet Cell Hyperplasia and Metaplasia in Horses with Recurrent Airway Obstruction Vet. Pathol., November 1, 2007; 44(6): 901 - 911. [Abstract] [Full Text] [PDF]

				P. G. Woodruff, H. A. Boushey, G. M. Dolganov, C. S. Barker, Y. H. Yang, S. Donnelly, A. Ellwanger, S. S. Sidhu, T. P. Dao-Pick, C. Pantoja, et al. From the Cover: Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids PNAS, October 2, 2007; 104(40): 15858 - 15863. [Abstract] [Full Text] [PDF]

				A. E. Hegab, T. Sakamoto, A. Nomura, Y. Ishii, Y. Morishima, T. Iizuka, T. Kiwamoto, Y. Matsuno, S. Homma, and K. Sekizawa Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis: The Role of hCLCA1 Chest, April 1, 2007; 131(4): 1149 - 1156. [Abstract] [Full Text] [PDF]

				L. Mundhenk, M. Alfalah, R. C. Elble, B. U. Pauli, H. Y. Naim, and A. D. Gruber Both Cleavage Products of the mCLCA3 Protein Are Secreted Soluble Proteins J. Biol. Chem., October 6, 2006; 281(40): 30072 - 30080. [Abstract] [Full Text] [PDF]

				M. J. Holtzman, J. T. Battaile, and A. C. Patel Immunogenetic Programs for Viral Induction of Mucous Cell Metaplasia Am. J. Respir. Cell Mol. Biol., July 1, 2006; 35(1): 29 - 39. [Full Text] [PDF]

				D. J. Erle and G. Zhen The asthma channel?: stay tuned . . . Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1181 - 1182. [Full Text] [PDF]

				T. Nakano, H. Inoue, S. Fukuyama, K. Matsumoto, M. Matsumura, M. Tsuda, T. Matsumoto, H. Aizawa, and Y. Nakanishi Niflumic Acid Suppresses Interleukin-13-induced Asthma Phenotypes Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1216 - 1221. [Abstract] [Full Text] [PDF]

				A. C. Patel, J. D. Morton, E. Y. Kim, Y. Alevy, S. Swanson, J. Tucker, G. Huang, E. Agapov, T. E. Phillips, M. E. Fuentes, et al. Genetic segregation of airway disease traits despite redundancy of calcium-activated chloride channel family members Physiol Genomics, May 16, 2006; 25(3): 502 - 513. [Abstract] [Full Text] [PDF]

				M. C. Rose and J. A. Voynow Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease Physiol Rev, January 1, 2006; 86(1): 245 - 278. [Abstract] [Full Text] [PDF]

				P. Thai, Y. Chen, G. Dolganov, and R. Wu Differential Regulation of MUC5AC/Muc5ac and hCLCA-1/mGob-5 Expression in Airway Epithelium Am. J. Respir. Cell Mol. Biol., December 1, 2005; 33(6): 523 - 530. [Abstract] [Full Text] [PDF]

				F. Brouillard, N. Bensalem, A. Hinzpeter, D. Tondelier, S. Trudel, A. D. Gruber, M. Ollero, and A. Edelman Blue Native/SDS-PAGE Analysis Reveals Reduced Expression of the mClCA3 Protein in Cystic Fibrosis Knock-out Mice Mol. Cell. Proteomics, November 1, 2005; 4(11): 1762 - 1775. [Abstract] [Full Text] [PDF]

				A. Robichaud, S. A. Tuck, S. Kargman, J. Tam, E. Wong, M. Abramovitz, J. Mortimer, H. E. Burston, P. Masson, J. Hirota, et al. Gob-5 Is Not Essential for Mucus Overproduction in Preclinical Murine Models of Allergic Asthma Am. J. Respir. Cell Mol. Biol., September 1, 2005; 33(3): 303 - 314. [Abstract] [Full Text] [PDF]

				F. Anton, I. Leverkoehne, L. Mundhenk, W. B. Thoreson, and A. D. Gruber Overexpression of eCLCA1 in Small Airways of Horses with Recurrent Airway Obstruction J. Histochem. Cytochem., August 1, 2005; 53(8): 1011 - 1021. [Abstract] [Full Text] [PDF]

				A. Gibson, A. P. Lewis, K. Affleck, A. J. Aitken, E. Meldrum, and N. Thompson hCLCA1 and mCLCA3 Are Secreted Non-integral Membrane Proteins and Therefore Are Not Ion Channels J. Biol. Chem., July 22, 2005; 280(29): 27205 - 27212. [Abstract] [Full Text] [PDF]

				M. E. Loewen and G. W. Forsyth Structure and Function of CLCA Proteins Physiol Rev, July 1, 2005; 85(3): 1061 - 1092. [Abstract] [Full Text] [PDF]

				C. Stellato Post-transcriptional and Nongenomic Effects of Glucocorticoids Proceedings of the ATS, November 1, 2004; 1(3): 255 - 263. [Abstract] [Full Text] [PDF]

				S. R. Evans, W. B. Thoreson, and C. L. Beck Molecular and Functional Analyses of Two New Calcium-activated Chloride Channel Family Members from Mouse Eye and Intestine J. Biol. Chem., October 1, 2004; 279(40): 41792 - 41800. [Abstract] [Full Text] [PDF]

				K. Hashimoto, B. S. Graham, S. B. Ho, K. B. Adler, R. D. Collins, S. J. Olson, W. Zhou, T. Suzutani, P. W. Jones, K. Goleniewska, et al. Respiratory Syncytial Virus in Allergic Lung Inflammation Increases Muc5ac and Gob-5 Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 306 - 312. [Abstract] [Full Text] [PDF]

				A E Hegab, T Sakamoto, Y Uchida, A Nomura, Y Ishii, Y Morishima, M Mochizuki, T Kimura, W Saitoh, H H Massoud, et al. CLCA1 gene polymorphisms in chronic obstructive pulmonary disease J. Med. Genet., March 1, 2004; 41(3): e27 - 27. [Full Text] [PDF]

				C. A. Bertrand, H. Danahay, C. T. Poll, C. Laboisse, U. Hopfer, and R. J. Bridges Niflumic acid inhibits ATP-stimulated exocytosis in a mucin-secreting epithelial cell line Am J Physiol Cell Physiol, February 1, 2004; 286(2): C247 - C255. [Abstract] [Full Text]

				A. L. Miller, R. M. Strieter, A. D. Gruber, S. B. Ho, and N. W. Lukacs CXCR2 Regulates Respiratory Syncytial Virus-Induced Airway Hyperreactivity and Mucus Overproduction J. Immunol., March 15, 2003; 170(6): 3348 - 3356. [Abstract] [Full Text] [PDF]

				M. J. Tobin Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 319 - 332. [Full Text] [PDF]