Association of Clara cell 10-kDa protein, spontaneous regression and sarcoidosis

Shijubo, Noriharu; Itoh, Yoshio; Shigehara, Katsunori; Yamaguchi, Tsutomu; Itoh, Kouichi; Shibuya, Yoshie; Takahashi, Ryuji; Ohchi, Takashi; Ohmichi, Mitsuhide; Hiraga, Yohmei; Abe, Shosaku

doi:10.1034/j.1399-3003.2000.016003414.x

Cited by 23 publications

(25 citation statements)

References 28 publications

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“…In all BAL fluid samples tested (n ϭ 5), a high concentration of guanylin [32.6 Ϯ 15.9 nmol͞ml (mean Ϯ SE)] was measured, ranging from 18.9 to 50.4 nmol͞ml BAL fluid sample, that obviously is considerably higher than the reported guanylin concentration in the circulation (23). Hence, the luminal presence of guanylin in terminal airways is basically consistent with the apical secretory characteristics of Clara cells (7) because they also may release the Clara cell protein CC10 luminally into the bronchiolar airways in high concentrations (24). Collectively, for the situation in situ, a luminocrine secretory and air-side acting mode of guanylin in Clara (Fig.…”

Section: Localization Of Guanylin In Clara Cells and Its Presence In mentioning

confidence: 55%

“…At present, the function of the Clara cells is discussed controversially but mainly correlated to a protective role against oxidative stress and inflammatory response in the respiratory tract and in production of surfactant in terminal airways (24). However, the present data conclusively reveal a particular function of Clara cells in the cGMP-mediated regulation of CFTR in small conducting airways implicating regulation of epithelial electrolyte͞fluid secretion in this critical location through an intriguing air-side route of activation of CFTR by guanylin; this clearly differs from the basolateral bloodside activation route mediated by cAMP and PKA (20).…”

Section: Discussionmentioning

confidence: 99%

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Clara cell impact in air-side activation of CFTR in small pulmonary airways

Kulaksiz

Schmid²,

Hönscheid³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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The Clara cells are nonciliated, nonmucous, secretory cells containing characteristic peptidergic granules; they constitute up to 80% of the epithelial cell population of the distal airways. Despite this exposed histotopology and abundance within the terminal airways where fluid secretion is of pivotal importance, the functional role of the Clara cells remained poorly understood. At the transcriptional, translational, and cellular levels, we provide evidence that the Clara cells are well equipped with the bioactive peptide guanylin and proteins of the cGMP-signaling system including guanylate cyclase C, cGMPdependent protein kinase II, and cystic fibrosis transmembrane conductance regulator (CFTR) together with the two CFTR scaffolding proteins EBP50͞NHERF and E3KARP͞NHERF-2 that are essential for proper function of CFTR. Guanylin was localized to secretory granules underneath the apical membrane of Clara cells and was, in addition, detected in high concentrations in bronchoalveolar lavage fluid, predicting release of the peptide luminally into the bronchiolar airways. On the other hand, the guanylin-receptor guanylate cyclase C, CFTR, and proteins linked to CFTR activation and function were all confined to the adluminal membrane of Clara cells, implicating an intriguing air-side route of action of guanylin. Whole-cell patch-clamp recordings in the Clara cell line H441 revealed that guanylin activates CFTR Cl ؊ conductance via the cGMP but not the cAMP-signaling pathway. Hence, in the critical location of distal airways in situ, the Clara cells may play the outstanding role of CFTR-dependent regulation of epithelial electrolyte͞water secretion through a sophisticated paracrine͞luminocrine mode of guanylin-induced CFTR activation.guanylin ͉ guanylate cyclase c ͉ lung ͉ cystic fibrosis ͉ electrolyte secretion

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Section: Localization Of Guanylin In Clara Cells and Its Presence In mentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Clara cell impact in air-side activation of CFTR in small pulmonary airways

Kulaksiz

Schmid²,

Hönscheid³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Decreased amounts of CC 16 in the airways probably reflect toxic effects on the epithelium that might cause both lower release of the protein as well as an increased leakage of the protein to the systemic circulation, thus leading to increased levels in both plasma and urine [18]. Lower levels of CC 16 have been found in bronchoalveolar lavage fluid from smokers [24] and asthmatics [25], and in NLF from subjects with asthma and rhinitis [6]. CC 16 belongs to the uteroglobin family of proteins and is thus related to mammaglobin B.…”

Section: Differences Between Smokers and Nonsmokersmentioning

confidence: 98%

Newly identified proteins in human nasal lavage fluid from non-smokers and smokers using two-dimensional gel electrophoresis and peptide mass fingerprinting

et al. 2002

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Human nasal lavage fluids (NLFs) were analyzed with two-dimensional gel electrophoresis (2-DE) and proteins were identified with peptide mass fingerprinting using matrix-assisted laser desoption/ionization time of flight mass spectrometry. In some cases, the identification was verified by analysis of post-source decay fragmentation spectra. Many of the identified proteins were new forms or fragments of previously found proteins (e.g. albumin, lactoferrin, cystatin, calgranulin, von Ebners gland protein and palate lung nasal epithelium clone), while others were proteins that have previously been indicated by 2-DE image matching or immunoblots (e.g. apolipoprotein AI, lysozyme C, and Clara cell secretory protein). Some new proteins, not shown before in 2-DE patterns of NLF were also found, e.g. mammaglobin B, (2)-microglobulin and immunoglobulin J chain. Of the identified NLF proteins many appear to be involved in inflammatory and immune responses. A study was therefore conducted to investigate if the levels of these proteins were changed in smokers compared to nonsmokers. It was found that NLF from smokers contained decreased levels of Clara cell secretory protein, and increased proportions of a truncated variant of lipocortin-1, three acidic forms of alpha(1)-antitrypsin, and one phosphorylated form of cystatin S. Furthermore, NLF from smokers contained increased proportions of a new variant of palate lung nasal epithelium clone (PLUNC), a recently identified airway irritation marker. The results demonstrate that 2-DE of NLF may be used to assess alterations of proteins or post-translationally modified proteins in smokers. Clara cell secretory protein (CC 16, CC 10) and lipocortin-1 are two anti-inflammatory, phospholipase A(2) inhibitory proteins, and alpha(1)-antitrypsin and cystatin S are two proteinase inhibitors. Changed levels of these proteins may therefore be of importance to the airway inflammation caused by smoking. The results also support the notion that PLUNC is involved in inflammatory responses in the upper airways.

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“…BAL analysis was performed on 58 sarcoid cases and 23 healthy subjects as previously described (26). Three 50-ml aliquots of 0.9% sterile saline were instilled into a bronchus in the right middle lobe through a fiberoptic bronchoscope in routine BAL analysis.…”

Section: Bal Analysismentioning

confidence: 99%

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

Shigehara

Shijubo²,

Ohmichi

et al. 2001

The Journal of Immunology

168

101

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Sarcoidosis is a systemic chronic granulomatous disease of unknown cause. Recent investigations revealed that the cytokine profile in inflamed lesions of sarcoidosis is Th1 dominant. To obtain better immunopathologic understanding of sarcoidosis, we examined the expression of IL-12 and IL-18 and their roles in IFN-γ production in pulmonary sarcoidosis. Sarcoid cases had significantly elevated levels of IL-12 (p40 and p70) and IL-18 in bronchoalveolar lavage (BAL) fluids compared with healthy subjects. IL-12 p70 and IL-18 were immunohistochemically expressed in the epithelioid cells and giant cells of sarcoid granulomas. Significant induction of IFN-γ, IL-12 p70, and IL-18 was observed from sarcoid BAL fluid cells with LPS stimulation, whereas LPS tended to induce only IL-12 p70 in BAL fluid cells from healthy subjects. Sarcoid cases had significantly greater IFN-γ induction with LPS stimulation than healthy subjects did. IL-18 mRNA expression was observed in freshly isolated sarcoid BAL fluid cells as well as in LPS-stimulated sarcoid BAL fluid cells, but IFN-γ and IL-12 mRNA expression was observed only in LPS-stimulated BAL fluid cells. Treatment with anti-IL-12- and anti-IL-18-neutralizing Abs significantly inhibited IFN-γ production from LPS-stimulated BAL fluid cells of sarcoid cases. Coadministration of rIL-12 or rIL-18 induced greater IFN-γ production in sarcoid BAL fluid cells than in normal BAL fluid cells. We concluded that bioactive IL-12 and IL-18 were produced in sarcoid BAL fluid cells and synergistically induced IFN-γ production, indicating important cytokines in the Th1 response of sarcoidosis.

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Association of Clara cell 10-kDa protein, spontaneous regression and sarcoidosis

Cited by 23 publications

References 28 publications

Clara cell impact in air-side activation of CFTR in small pulmonary airways

Clara cell impact in air-side activation of CFTR in small pulmonary airways

Newly identified proteins in human nasal lavage fluid from non-smokers and smokers using two-dimensional gel electrophoresis and peptide mass fingerprinting

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

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