Dataset Information

Mechanical compression reduces CC16 expression and disrupts metabolic homeostasis in airway epithelial cells

ABSTRACT: Recent evidence suggests that bronchial epithelial cells from asthmatic patients exhibit altered metabolic signatures. This metabolic shift of energetically demanding cells leads to increased inflammation, excessive reactive oxygen species production (ROS), and oxidative stress—all hallmarks of mitochondrial dysfunction. While mitochondrial dysfunction has been implicated in asthmatic epithelial cells, the mechanistic link between bronchoconstriction and these metabolic alterations remains poorly defined. Club cell secretory protein (CC16) is the most abundant protein found in the lung and exerts key anti-inflammatory and antioxidant functions, culminating in protection against airway remodeling. Decreased levels of CC16 are characteristic of asthma and worsening respiratory disease. Using a well-established transmembrane compression system to model bronchoconstriction coupled with mass spectrometry and quantitative proteomics, we investigated how modeling bronchoconstriction in airway cells impacts CC16 expression and cell metabolic pathway changes over time. Additionally, using rCC16, we examined the direct impact on airway cell metabolism. Using naïve mouse tracheal epithelial cells (MTECs) and normal human bronchial epithelial cells (HBECs), we observed that rCC16 induces the expression of proteins related to various metabolic pathways, such as glycolysis, gluconeogenesis, and the pentose phosphate pathway and that compression of airway cells results in acute decreases in CC16 expression, as well as decreases in metabolic processes. MTECs deficient in CC16 (CC16-/-) had lower mitochondrial oxygen consumption rate (OCR) compared to WT cells, both of which could be increased by exogenous addition of rCC16. Our findings suggest a novel role for CC16 in mediating airway epithelial cell metabolic processes, which could be decreased by bronchoconstrictive events in asthma patients.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Lung Cell Line

SUBMITTER: Paul Langlais

LAB HEAD: Julie Ledford

PROVIDER: PXD067703 | Pride | 2026-05-25

REPOSITORIES: Pride

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			Action	DRS
	20220331_R2D2_4653_1.raw	Raw
	20220331_R2D2_4653_1.raw__F001993_.mzid	Mzid
	20220331_R2D2_4653_1.raw__F001993_.mzid_20220331_R2D2_4653_1.raw__F001993_.MGF	Mzid
	20220331_R2D2_4653_2.raw	Raw
	20220331_R2D2_4653_2.raw__F001994_.mzid	Mzid

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Mechanical compression reduces CC16 expression and disrupts metabolic homeostasis in airway epithelial cells.

Berthiaume Fox Kayleigh A KA Iannuzo Natalie N Li Julia J Rojas-Quintero Joselyn J Kimura Hiroki H Santiago Raj Paul Victor PV Schnellmann Rick G RG Johnson Michael D L MDL Polverino Francesca F Langlais Paul R PR Kraft Monica M Park Jin-Ah JA Ledford Julie G JG

American journal of respiratory cell and molecular biology 20260519

Recent evidence suggests that bronchial epithelial cells from individuals with asthma exhibit altered metabolic signatures. This metabolic shift of energetically demanding cells leads to increased inflammation, excessive reactive oxygen species production (ROS), and oxidative stress-all hallmarks of mitochondrial dysfunction. While mitochondrial dysfunction has been implicated in disruption in epithelial cell function in asthma, the mechanistic link between bronchoconstriction observed in asthma ...[more]

PMID: 42154955

Similar Datasets

Project description:Rationale: CC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against the development of obstructive lung diseases and attenuate pulmonary pathogen burden. Despite recent advances in understanding CC16 effects in circulation, the biological mechanisms of CC16 in pulmonary epithelial responses have not been elucidated. Objectives: We sought to determine if CC16 deficiency impairs epithelial-driven host responses and identify novel receptors expressed within the pulmonary epithelium through which CC16 imparts activity. Methods: We utilized mass spectrometry and quantitative proteomics to investigate how CC16 deficiency impacts apically secreted pulmonary epithelial proteins. Mouse tracheal epithelial cells (MTECS), human nasal epithelial cells (HNECs) and mice were studied in naïve conditions and after Mp challenge. Measurements and Main Results: We identified 8 antimicrobial proteins significantly decreased by CC16-/- MTECS, 6 of which were validated by mRNA expression in Severe Asthma Research Program (SARP) cohorts. Short Palate Lung and Nasal Epithelial Clone 1 (SPLUNC1) was the most differentially expressed protein (66-fold) and was the focus of this study. Using a combination of MTECs and HNECs, we found that CC16 enhances pulmonary epithelial-driven SPLUNC1 expression via signaling through the receptor complex Very Late Antigen-2 (VLA-2) and that rCC16 given to mice enhances pulmonary SPLUNC1 production and decreases Mycoplasma pneumoniae (Mp) burden. Likewise, rSPLUNC1 results in decreased Mp burden in mice lacking CC16 mice. The VLA-2 integrin binding site within rCC16 is necessary for induction of SPLUNC1 and the reduction in Mp burden. Conclusions: Our findings demonstrate a novel role for CC16 in epithelial-driven host defense by up-regulating antimicrobials and define a novel epithelial receptor for CC16, VLA-2, through which signaling is necessary for enhanced SPLUNC1 production.