Clara cell protein (CC-16) induces a phospholipase A2-mediated inhibition of fibroblast migration in vitro.

Lesur, Olivier; Bernard, Alfred; Arsalane, K.; Lauwerys, Robert; Bégin, Raymond; Cantin, André M.; Lane, Denis

doi:10.1164/ajrccm.152.1.7541278

Cited by 138 publications

(130 citation statements)

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“…61 Interestingly, CCSP can also suppress fibroblast migration. 62 Additionally, stressed airway epithelial cells release profibrotic factors that can induce a remodeling response by fibroblasts, 63 and delayed lung epithelial repair promotes fibroblast proliferation. 64,65 Thus, evidence is mounting that epithelial damage promotes fibroproliferation.…”

Section: Discussionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Chen

McGuire

Hackman

et al. 2008

The American Journal of Pathology

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Obliterative bronchiolitis (OB) is the histopathological finding in chronic lung allograft rejection. Mounting evidence suggests that epithelial damage drives the development of airway fibrosis in OB. Tissue inhibitor of metalloproteinase (TIMP)-1 expression increases in lung allografts and is associated with the onset of allograft rejection. Furthermore, in a mouse model of OB, airway obliteration is reduced in TIMP-1-deficient mice. Matrilysin (matrix metallproteinase-7) is essential for airway epithelial repair and is required for the re-epithelialization of airway wounds by facilitating cell migration; therefore, the goal of this study was to determine whether TIMP-1 inhibits re-epithelialization through matrilysin. We found that TIMP-1 and matrilysin co-localized in the epithelium of human lungs with OB and both co-localized and co-immunoprecipitated in wounded primary airway epithelial cultures. TIMP-1-deficient cultures migrated faster, and epithelial cells spread to a greater extent compared with wild-type cultures. TIMP-1 also inhibited matrilysin-mediated cell migration and spreading in vitro. In vivo, TIMP-1 deficiency enhanced airway re-epithelialization after naphthalene injury. Furthermore, TIMP-1 and matrilysin co-localized in airway epithelial cells adjacent to the wound edge. Our data demonstrate that TIMP-1 interacts with matrix metalloproteinases and regulates matrilysin activity during airway epithelial repair. Furthermore, we speculate that TIMP-1 overexpression restricts airway re-epithelialization by inhibiting matrilysin activity, contributing to a stereotypic injury response that promotes airway fibrosis via bronchiole airway epithelial damage and obliteration. Bronchiolitis obliterans syndrome (BOS) is the manifestation of chronic lung rejection and limits the 5-year survival after lung transplant to less than 50%.1 In comparison, transplantations of other solid organs, such as the heart, pancreas, liver, and kidneys, have 5-year survival rates exceeding 70%.2 Obliterative bronchiolitis (OB) is the histopathological equivalent of BOS and is characterized by small airway fibrosis that contributes to progressive respiratory failure and death.3 Although the pathogenesis of OB is poorly understood, evidence suggests that the primary immunological target in the lung allograft is the airway epithelium. 4 -7 Moreover, aberrant airway re-epithelialization is apparently sufficient for the progression of fibrosis during the allograft rejection process. -13The airway epithelium is an important barrier in the innate defenses of the lung.14 After lung transplantation, persistent allo-dependent (eg, acute rejection) and alloindependent (eg, infection, ischemia) pressures on the airway epithelium necessitate rapid re-epithelialization to prevent further damage that can contribute to inflammation and fibrosis.3 Disturbances in the epithelial barrier are quickly repaired through coordinated processes by which epithelial cells bordering the injury quickly spread over the denuded basement membrane. [15][...

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Section: Discussionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Chen

McGuire

Hackman

et al. 2008

The American Journal of Pathology

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“…Even micromolar concentrations of CC16 have been shown to inhibit chemotaxis of neutrophils and monocytes (Laing et al 1998). The protein is known to control the proliferation and migration of fibroblasts in the lungs (Lesur et al 1995). In addition, it also inhibits the activity of secreted and intracellular phospholipase A 2 , thereby limiting the synthesis of prostaglandins and leukotrienes (Levin et al 1986).…”

Section: Introductionmentioning

confidence: 99%

Association of an intragenic microsatellite marker in the CC16 gene with asthma in the Indian population

Sharma

Ghosh

2004

J Hum Genet

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The gene for Clara cell secretory protein (CC16) is an ideal candidate for investigating genetic predisposition to asthma because of its role in the airway as an antiinflammatory molecule, differences in its levels between asthmatics and healthy controls, and its genetic location (11q13). We investigated the association of an SNP (A38G) and an intragenic repeat polymorphism in the CC16 gene with asthma and its associated traits, such as total serum IgE levels, in a case control as well as in a family based study design. A significant association was observed for the microsatellite repeat at the level of alleles and genotypes with asthma (P<0.05) in both the study designs. However, no association was observed for the A38G SNP with asthma. When haplotypes were constructed for these two loci and compared, the haplotype A_18 was found at higher frequency in patients (OR=1.59, 95%CI=1.08, 2.33, P=0.016). Also, in the family based design, a biased transmission was observed for haplotypes from parents to affected offspring (P=0.003). Individually, haplotype A_18 showed preferential transmission (82.6%) to affected offspring (P=0.001), thereby confirming the case-control results. In summary, this is the first study identifying the CC16 gene to be associated with asthma in the Indian population.

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“…CC10 also inhibits fibroblast chemotaxis, which is related to a blockage of the secretory phospholipase A 2 (PLA 2 ; Ref. 17). Similarly, studies have suggested that CC10 is able to modulate the activity of IFN-␥ (18).…”

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confidence: 97%

Cutting Edge: Altered Pulmonary Eosinophilic Inflammation in Mice Deficient for Clara Cell Secretory 10-kDa Protein

Chen

Zhang

Myers

et al. 2001

The Journal of Immunology

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Clara cell secretory protein (CC10) is a steroid-inducible protein, and its in vivo function is currently unclear. The role of CC10 in modulation of pulmonary allergic inflammation was examined in mice deficient for the CC10 gene. Wild-type and homozygous CC10-deficient mice were sensitized with an Ag, OVA, and challenged with either OVA or saline. When compared with that seen in wild-type mice, a significantly higher level of pulmonary eosinophilia was found in Ag-sensitized and challenged CC10-deficient mice. Significantly increased levels of Th2 cytokines IL-4, IL-5, IL-9, and IL-13 were also found in CC10-deficient mice. In addition, an increased level of eotaxin, but not RANTES, was also seen in CC10-deficient mice. No significant difference was observed in the level of a Th1 cytokine, IFN-γ, between different groups of mice. These results provided the first in vivo evidence that CC10 plays a role in the modulation of pulmonary allergic inflammation.

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Clara cell protein (CC-16) induces a phospholipase A2-mediated inhibition of fibroblast migration in vitro.

Cited by 138 publications

References 0 publications

Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity

Association of an intragenic microsatellite marker in the CC16 gene with asthma in the Indian population

Cutting Edge: Altered Pulmonary Eosinophilic Inflammation in Mice Deficient for Clara Cell Secretory 10-kDa Protein

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