Human airway surface epithelial regeneration is delayed and abnormal in cystic fibrosis

Hajj, Rodolphe; Lesimple, Pierre; Nawrocki‐Raby, Béatrice; Birembaut, Philippe; Puchelle, Édith; Coraux, Christelle

doi:10.1002/path.2118

Cited by 89 publications

(107 citation statements)

References 55 publications

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“…These results may relate to the hyper-proliferative state previously described in CF HAECs (Voynow et al, 2005;Hajj et al, 2007). The rapid onset of proliferation in CF HAECs could be explained, in part, by increased amount of progenitor cells in these cultures.…”

Section: Discussionsupporting

confidence: 53%

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Cx26 regulates proliferation of repairing basal airway epithelial cells

Crespin

Bacchetta

Saab

et al. 2014

The International Journal of Biochemistry & Cell Biology

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The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation.Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs.We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation.

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Section: Discussionsupporting

confidence: 53%

“…We also evaluated whether KLF4 regulates Cx26 expression in repairing HAECs. Because a hyperproliferative state has been described in CF HAECs (Voynow et al, 2005;Hajj et al, 2007), we investigated the expression of Cx26 and KLF4 in this disease as well.…”

Section: Introductionmentioning

confidence: 99%

Cx26 regulates proliferation of repairing basal airway epithelial cells

Crespin

Bacchetta

Saab

et al. 2014

The International Journal of Biochemistry & Cell Biology

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“…The human airway epithelium can be fully regenerated in vitro from isolated HAECs maintained in culture in an air-liquid interface condition. 20 In this model, we observed a progressive regeneration of pseudostratified epithelium after 4 to 6 weeks ( Figure 3A). By using immunofluorescence and RT-PCR techniques, we observed that the expression of ␣7 nAChR in the basal layers of the epithelium was maximal in steps II and III (appearance of the first ciliated cells) and paralleled the expression of CK14, a marker of airway basal cells, 29 suggesting that ␣7 nAChR expression in basal cells is essential during the initial step of epithelial differentiation and the establishment of the basal cell layer.…”

Section: ␣7 Nachr Expression Is Associated With the Differentiation Omentioning

confidence: 72%

“…2,19,20 After 5, 7, 9, 11, 16, 23, 30, and 33 days, cells were detached with trypsin and counted with the ADAM-MC apparatus (Labtech, France).…”

Section: Epithelial Cell Isolation and Culturementioning

confidence: 99%

α7 Nicotinic Acetylcholine Receptor Regulates Airway Epithelium Differentiation by Controlling Basal Cell Proliferation

Maouche

Polette

Jolly

et al. 2009

The American Journal of Pathology

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Airway epithelial basal cells are known to be critical for regenerating injured epithelium and maintaining tissue homeostasis. Recent evidence suggests that the ␣7 nicotinic acetylcholine receptor (nAChR), which is highly permeable to Ca 2؉ , is involved in lung morphogenesis. Here, we have investigated the potential role of the ␣7 nAChR in the regulation of airway epithelial basal cell proliferation and the differentiation of the human airway epithelium. In vivo during fetal development and in vitro during the regeneration of the human airway epithelium, ␣7 nAChR expression coincides with epithelium differentiation. Inactivating ␣7 nAChR function in vitro increases cell proliferation during the initial steps of the epithelium regeneration, leading to epithelial alterations such as basal cell hyperplasia and squamous metaplasia, remodeling observed in many bronchopulmonary diseases. The regeneration of the airway epithelium after injury in ␣7 The respiratory epithelium, which is constantly exposed to airborne pollutants, is frequently injured, which results in altered epithelial functions. To restore these functions, the respiratory epithelium must undergo rapid repair via epithelial cell spreading and migration and regenerate its structure via basal cell proliferation and differentiation.

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“…28 -30 However, a direct interaction between TIMP-1 and a MMP has not been demonstrated in a physiological model. TIMP-1 expression by epithelial cells increases during epithelial regeneration in various wound-healing and disease models, [31][32][33][34][35][36][37][38] including lung transplantation and during the onset of BOS. 39 -42 Transgenic overexpression of TIMP-1 by keratinocytes delays skin wound closure in vivo, 43 suggesting that the endogenous protein functions to govern re-epithelialization.…”

mentioning

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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Human airway surface epithelial regeneration is delayed and abnormal in cystic fibrosis

Cited by 89 publications

References 55 publications

Cx26 regulates proliferation of repairing basal airway epithelial cells

Cx26 regulates proliferation of repairing basal airway epithelial cells

α7 Nicotinic Acetylcholine Receptor Regulates Airway Epithelium Differentiation by Controlling Basal Cell Proliferation

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

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