Biology subjects

van Schadewijk, A.

Publications and source records attributed to van Schadewijk, A..

3 recordsLinked to original sources

bioRxiv2024

Cigarette smoke induces PPP1R15A via oxidative stress to modulate inflammatory cytokine production by bronchial epithelial cells

Cigarette smoke is the principal cause of chronic obstructive pulmonary disease (COPD) in western societies. It induces pulmonary inflammation and activates multiple stress signaling pathways in bronchial epithelial cells, including the integrated stress response (ISR). The ISR is triggered by phosphorylation of the translation initiation factor eIF2 in response to a variety of insults and is functionally antagonised by the eIF2 phosphatase subunit PPP1R15A. Deletion of PPP1R15A exaggerates the ISR and in many models protects against a cellular stress. However, loss of PPP1R15A was recently shown to exaggerate pulmonary fibrosis in bleomycin-challenged mice. We therefore wished to understand the role of PPP1R15A in the pulmonary response to cigarette smoke, which can cause both COPD and pulmonary fibrosis. Whole cigarette smoke rapidly activated the ISR in mucociliary differentiated human primary bronchial epithelial cells with those from COPD patients exhibiting higher levels of ISR. Acute exposure to cigarette smoke condensate induced a pro-inflammatory cytokine response accompanied by PPP1R15A expression. In this model, PPP1R15A induction was independent of eIF2 phosphorylation but was suppressed by antioxidants suggesting a response to oxidative stress. In vivo studies in mice revealed that PPP1R15A deficiency enhanced the secretion of proinflammatory cytokines in mice, suggesting a regulatory role for PPP1R15A in modulating the inflammatory response to smoke. Taken together, these data suggest that PPP1R15A is induced by cigarette smoke by an ISR-independent oxidative stress mechanism and ameliorates the pro-inflammatory cytokine response to cigarette smoke.

cell biology↗

bioRxiv2023

Structure-function relationships of mucociliary clearance in the human airways

Mucociliary clearance is a vital defense mechanism of the human airways, protecting against harmful particles and infections. When this process fails, it contributes to respiratory diseases like chronic obstructive pulmonary disease (COPD) and asthma. While advances in single-cell transcriptomics have revealed the complexity of airway composition, much of what we know about how airway structure impacts clearance relies on animal studies. This limits our ability to create accurate human-based models of airway diseases. Here we show that the airways in female rats and in humans exhibit species-specific differences in the distribution of ciliated and secretory cells as well as in ciliary beat, resulting in significantly higher clearance effectiveness in humans. We further reveal that standard lab-grown cultures exhibit lower clearance effectiveness compared to human airways, and we identify the underlying structural differences. By combining diverse experiments and physics-based modeling, we establish universal benchmarks to assess human airway function, interpret preclinical models, and better understand disease-specific impairments in mucociliary clearance.

biophysics↗

bioRxiv2021

Breathing on Chip: Biomechanical forces change airway epithelial cell biology ina human Airway Lung-Chip

Human lung function is intricately linked to blood flow and breathing cycles, but it remains unknown how these dynamic cues shape human airway epithelial biology. Here we report a state-of-the-art protocol for studying effects of physiological airflow and stretch on differentiation, cellular composition, and mucociliary clearance of human primary airway epithelial cells cultured on a perfused airway chip. Perfused epithelial tissue cultures developed a large airway-like cellular composition with accelerated maturation and polarization of mucociliary clearance when compared to traditional (static) culture methods. Additional application of airflow and stretch to the airway chip resulted in a cellular composition more comparable to the small(er) airways, reduced baseline secretion of interleukin-8 and other inflammatory proteins, and reduced gene expression of matrix metalloproteinase (MMP) 9, fibronectin, and other extracellular matrix factors. These results indicate that breathing-like mechanical stimuli are important modulators of airway epithelial cell differentiation and homeostasis and that their fine-tuned application could generate models of specific epithelial regions, pathologies, and mucociliary (dys)function.

cell biology↗