Pathophysiology of Lung Disease and Wound Repair in Cystic Fibrosis

Conese, Massimo; Gioia, Sante Di

doi:10.3390/pathophysiology28010011

Cited by 18 publications

(16 citation statements)

References 235 publications

(312 reference statements)

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“…Mature primary cystic fibrosis bronchial epithelium displays normal levels of epithelial markers; however, increased mesenchymal markers are present and TEER is decreased relative to non-cystic fibrosis bronchial epithelia. 33 Collectively, these data support the notion that vocal fold re-epithelialization may not be a definitive endpoint in the healing process irrespective of the extent of the injury. The epithelium appears to have altered barrier function in the context of a clinically healed post-surgical injury.…”

Section: Discussionsupporting

confidence: 67%

Epithelial response to vocal fold microflap injury in a preclinical model

et al. 2022

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Objectives Functional outcomes following microflap surgery for vocal fold pathology are favorable. Although the stratified squamous epithelium appears to heal rapidly, persistent physiologic tissue alterations are likely. We sought to elucidate key biochemical processes including recruitment of immune cells, regulation of cellular junction proteins, and long‐term alterations to epithelial tissue permeability following microflap with an eye toward enhanced clinical outcomes. Methods Forty New Zealand rabbits were assigned to eight groups (n = 5/group): no‐injury control or bilateral microflap with survival for 0 h, 12 h, 1 day, 3 days, 7 days, 30 days, and 60 days post‐microflap. The epithelium was dissected from one vocal fold and transepithelial resistance was quantified. The contralateral fold was subjected to transmission electron microscopy. Images were evaluated by a blinded rater and paracellular space dilation was quantified using ImageJ. Immune cell infiltration was evaluated and recorded qualitatively. Results Increased innate immune response was observed 12 h as well as 7 and 30 days after microflap. At 60 days following injury, decreased epithelial resistance was observed. Paracellular spaces were dilated at all time‐points following injury. Conclusions The vocal fold epithelium was significantly altered at 60 days following microflap. The implications for this tissue phenotype are unclear. However, compromised epithelial barrier function is implicated in various diseases and may increase the risk of subsequent injury. Level of Evidence NA Laryngoscope, 133:350–356, 2023

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Section: Discussionsupporting

confidence: 67%

Epithelial response to vocal fold microflap injury in a preclinical model

et al. 2022

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“…The defect in wound repair presented by us [ 22 ] and others in various cell models of CF primary and immortalized cell lines [ 19 , 21 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ] strongly suggest that the lack/dysfunction of the CFTR protein may play an essential role. Orkambi ® (lumacaftor/ivacaftor) has been previously shown to significantly increase wound repair rates over a period of 6 h with CF primary airway epithelial cells [ 19 ].…”

Section: Discussionmentioning

confidence: 97%

Elexacaftor/Tezacaftor/Ivacaftor Accelerates Wound Repair in Cystic Fibrosis Airway Epithelium

Laselva

Conese

2022

JPM

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Background: Cystic fibrosis (CF) airway epithelium shows alterations in repair following damage. In vitro studies showed that lumacaftor/ivacaftor (Orkambi) may favor airway epithelial integrity in CF patients. Our aim was to evaluate the effect of the novel triple combination elexacaftor/tezacaftor/ivacaftor (ETI) on wound repair in CF airway epithelial cells. Methods: A tip-based scratch assay was employed to study wound repair in monolayers of CFBE14o- cells overexpressing the F508del mutation. ETI was added during wound repair. Results: ETI efficiently rescued CFTR F508del maturation and activity, accelerated wound closure and increased wound healing rates of the injured CF cell monolayers. Conclusions: The triple corrector/potentiator combination ETI shows promise in ameliorating wound healing of the airway epithelium in F508del patients.

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“…GJs have been shown to be involved in the wound healing of skin and cornea [ 56 ], with a complex expression pattern of CXs at various stages of wound repair [ 57 ]. However, scant information is available for the repair of a wounded airway epithelium [ 58 , 59 ]. Given the recognized importance of epithelial junctions in the pathophysiology of CF [ 60 ], this gap should be filled.…”

Section: Discussionmentioning

confidence: 99%

Human Amniotic Mesenchymal Stem Cells and Fibroblasts Accelerate Wound Repair of Cystic Fibrosis Epithelium

Beccia

Daniello

Laselva

et al. 2022

Life

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Cystic fibrosis (CF) airways are affected by a deranged repair of the damaged epithelium resulting in altered regeneration and differentiation. Previously, we showed that human amniotic mesenchymal stem cells (hAMSCs) corrected base defects of CF airway epithelial cells via connexin (CX)43-intercellular gap junction formation. In this scenario, it is unknown whether hAMSCs, or fibroblasts sharing some common characteristics with MSCs, can operate a faster repair of a damaged airway epithelium. A tip-based scratch assay was employed to study wound repair in monolayers of CFBE14o- cells (CFBE, homozygous for the F508del mutation). hAMSCs were either co-cultured with CFBE cells before the wound or added to the wounded monolayers. NIH-3T3 fibroblasts (CX43+) were added to wounded cells. HeLa cells (CX43-) were used as controls. γ-irradiation was optimized to block CFBE cell proliferation. A specific siRNA was employed to downregulate CX43 expression in CFBE cells. CFBE cells showed a delayed repair as compared with wt-CFTR cells (16HBE41o-). hAMSCs enhanced the wound repair rate of wounded CFBE cell monolayers, especially when added post wounding. hAMSCs and NIH-3T3 fibroblasts, but not HeLa cells, increased wound closure of irradiated CFBE monolayers. CX43 downregulation accelerated CFBE wound repair rate without affecting cell proliferation. We conclude that hAMSCs and fibroblasts enhance the repair of a wounded CF airway epithelium, likely through a CX43-mediated mechanism mainly involving cell migration.

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Pathophysiology of Lung Disease and Wound Repair in Cystic Fibrosis

Cited by 18 publications

References 235 publications

Epithelial response to vocal fold microflap injury in a preclinical model

Epithelial response to vocal fold microflap injury in a preclinical model

Elexacaftor/Tezacaftor/Ivacaftor Accelerates Wound Repair in Cystic Fibrosis Airway Epithelium

Human Amniotic Mesenchymal Stem Cells and Fibroblasts Accelerate Wound Repair of Cystic Fibrosis Epithelium

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