Dataset Information

Soluble Wood Smoke Extract Promotes Barrier Dysfunction in Alveolar Epithelial Cells through a MAPK Signaling Pathway.

ABSTRACT: Wildfire smoke induces acute pulmonary distress and is of particular concern to risk groups such as the sick and elderly. Wood smoke (WS) contains many of the same toxic compounds as those found in cigarette smoke (CS) including polycyclic aromatic hydrocarbons, carbon monoxide, and free radicals. CS is a well-established risk factor for respiratory diseases such as asthma and COPD. Limited studies investigating the biological effects of WS on the airway epithelium have been performed. Using a cell culture-based model, we assessed the effects of a WS-infused solution on alveolar epithelial barrier function, cell migration, and survival. The average geometric mean of particles in the WS was 178?nm. GC/MS analysis of the WS solution identified phenolic and cellulosic compounds. WS exposure resulted in a significant reduction in barrier function, which peaked after 24?hours of continuous exposure. The junctional protein E-cadherin showed a prominent reduction in response to increasing concentrations of WS. Furthermore, WS significantly repressed cell migration following injury to the cell monolayer. There was no difference in cell viability following WS exposure. Mechanistically, WS exposure induced activation of the p44/42, but not p38, MAPK signaling pathway, and inhibition of p44/42 phosphorylation prevented the disruption of barrier function and loss of E-cadherin staining. Thus, WS may contribute to the breakdown of alveolar structure and function through a p44/42 MAPK-dependent pathway and may lead to the development and/or exacerbation of respiratory pathologies with chronic exposure.

SUBMITTER: Zeglinski MR

PROVIDER: S-EPMC6624307 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Soluble Wood Smoke Extract Promotes Barrier Dysfunction in Alveolar Epithelial Cells through a MAPK Signaling Pathway.

Zeglinski Matthew R MR Turner Christopher T CT Zeng Rui R Schwartz Carley C Santacruz Stephanie S Pawluk Megan A MA Zhao Hongyan H Chan Arthur W H AWH Carlsten Christopher C Granville David J DJ

Scientific reports 20190711 1

Wildfire smoke induces acute pulmonary distress and is of particular concern to risk groups such as the sick and elderly. Wood smoke (WS) contains many of the same toxic compounds as those found in cigarette smoke (CS) including polycyclic aromatic hydrocarbons, carbon monoxide, and free radicals. CS is a well-established risk factor for respiratory diseases such as asthma and COPD. Limited studies investigating the biological effects of WS on the airway epithelium have been performed. Using a c ...[more]

PMID: 31296909

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Project description:BackgroundIndividuals with respiratory disease are being increasingly exposed to wildfire smoke as populations encroach further into forested regions and climate change continues to bring higher temperatures with lower rainfall. Frequent exposures have significant potential to accelerate conditions such as chronic obstructive pulmonary disease (COPD) which is characterised by an exaggerated inflammatory response to environmental stimuli. Here we employ models of human airway epithelium exposed to wildfire smoke-extract (WFSE) to examine modulation in airway epithelial cell (AEC) survival, fragility and barrier function.MethodsSubmerged cultures of small airway epithelial cells (SAEC) and differentiated air-liquid interface (ALI) cultures of primary bronchial AEC (bAEC) were treated for 1-24 h with 1-10% WFSE generated from plant species found in the Australian bushland. Autophagy (LC3-II and Sequestosome), apoptosis (Poly-(ADP)-Ribose Polymerase (PARP) cleavage) and tight junction proteins were measured using western blot. Barrier function was assessed via permeability of fluorescein tracers and measuring trans-epithelial electrical resistance. The production of IL-6 was assessed using ELISA.ResultsPrimary epithelial models exposed to WFSE exhibited a significant blockade in autophagy as evidenced by an increase in LC3-II coupled with a concomitant elevation in Sequestosome abundance. These exposures also induced significant PARP cleavage indicative of apoptotic changes. ALI cultures of bAEC treated with 5% WFSE demonstrated barrier dysfunction with significant increases in paracellular molecular permeability and ionic conductance, and a reduction in the abundance of the tight junction proteins ZO-1 and Claudin-1. These cultures also exhibited increased IL-6 secretion consistent with the aberrant and pro-inflammatory repair response observed in the COPD airways. Further, blocks in autophagy and barrier disruption were significantly elevated in response to WFSE in comparison to similar exposures with cigarette smoke-extract.ConclusionWFSE inhibits autophagic flux and induces barrier dysfunction in the airway epithelium. As autophagy is a central regulator of cellular repair, viability, and inflammation, targeting the block in autophagic flux may ameliorate the consequences of wildfire smoke-exposure for individuals with pre-existing respiratory conditions.

Project description:The blood-brain barrier (BBB) dysfunction is an initial event of various neuroinflammatory diseases. However, the absence of reliable markers and mechanisms for BBB damage greatly limits the diagnosis and treatment of neuroinflammatory diseases. Soluble CD146 (sCD146) is mainly derived from vascular endothelial cells (ECs) and highly elevated in inflammatory settings. Based on a small cohort, our previous study showed that sCD146 is elevated in the cerebrospinal fluid (CSF) of multiple sclerosis (MS), which is accompanied with BBB damage. Nevertheless, whether sCD146 monitors and regulates the BBB dysfunction remains unknown. Methods: Coupled serum and CSF samples from patients with or without neuroinflammatory diseases were collected via multicenter collaborations. sCD146 was measured by sandwich ELISA using anti-CD146 antibodies AA1 and AA98, both of which were generated in our laboratory. The correlations between sCD146 and other clinical parameters or inflammatory factors were analyzed by Spearman's correlation coefficient analysis. The role of sCD146 on BBB function was examined in an in vitro BBB model. Results: Between July 20, 2011, and February 31, 2017, we collected coupled serum and CSF samples from 823 patients, of which 562 (68.3%) had neuroinflammatory diseases, 44 (5.3%) had remitting MS, and 217 (26.4%) had non-inflammatory neurological diseases (NIND). We found that sCD146 in CSF, but not in serum, is abnormally elevated in neuroinflammatory diseases (37.3 ± 13.3 ng/mL) compared with NIND (4.7 ± 2.9 ng/mL) and remitting MS (4.6 ± 3.5 ng/mL). Abnormally elevated CSF sCD146 is significantly correlated with the hyperpermeability-related clinical parameters of BBB and neuroinflammation-related factors. Moreover, CSF sCD146 shows higher sensitivity and specificity for evaluating BBB damage. Using an in vitro BBB model, we found that sCD146 impairs BBB function by promoting BBB permeability via an association with integrin ?v?1. Blocking integrin ?v?1 significantly attenuates sCD146-induced hyperpermeability of the BBB. Conclusion: Our study provides convincing evidence that CSF sCD146 is a sensitive marker of BBB damage and neuroinflammation. Furthermore, sCD146 is actively involved in BBB dysfunction.

Dataset Information

Soluble Wood Smoke Extract Promotes Barrier Dysfunction in Alveolar Epithelial Cells through a MAPK Signaling Pathway.

Publications

Soluble Wood Smoke Extract Promotes Barrier Dysfunction in Alveolar Epithelial Cells through a MAPK Signaling Pathway.

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