TD-0903, an inhaled JAK inhibitor in development for COVID-19, blocks ARDS-relevant hyperinflammation and lung injury in primary human immune and airway epithelial cells

Abstract Background: Lycium barbarum berries have been utilized in Asia for many years. However, the mechanisms of its lung-defensive properties are indeterminate. Methods: We investigate whether L. barbarum polysaccharide could weaken Pseudomonas aeruginosa infection-induced lung injury. Mice primary air-liquid interface epithelial cultures were pretreated with L. barbarum polysaccharide (LBP) and subsequently treated with pyocyanin (PCN). Lung injury, including apoptosis, inflammation, and oxidative stress, was estimated by western blot, ELISA and Q-PCR. Flow cytometry was used to test cell apoptosis. Moreover, Balb/c mice were used to evaluate the tissue injury. We used hematoxylin-eosin staining and immunofluorescence to detect the expression of related proteins and tissue damage in mouse lungs and spleen. Results: The flow cytometric analysis shows the potential of Lycium barbarum polysaccharide (LBP) to reduce time-dependent cell death by PCN. Mechanistically, LBP reduces PCN-induced expression of proapoptotic proteins, caspase3, and induces the activation of Bcl-2 in mice bronchial epithelial cells. Similarly, LBP reduces PCN-induced intracellular reactive oxygen species (ROS) production. Moreover, LBP inhibits the production of inflammatory cytokines, IL-1β, TNF, IL-6, and IL-8. Conclusion: Our study confirms the ability of LBP to retard PCN-induced injury in mice lung and spleen. Inhibition of PCN-induced lung injury by LBP is capable of protecting mice cells from injury.

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Bacterial extracellular vesicles isolated from organic dust induce neutrophilic inflammation in the lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00107.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. L893-L907 ◽

Cited By ~ 1

Author(s):

Velmurugan Meganathan ◽

Regina Moyana ◽

Kartiga Natarajan ◽

Weshely Kujur ◽

Shilpa Kusampudi ◽

...

Keyword(s):

Epithelial Cells ◽

Lung Injury ◽

Extracellular Vesicles ◽

Inflammatory Mediators ◽

Lung Inflammation ◽

Respiratory Diseases ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Organic Dust ◽

Tnf Α

Inhalation of organic dust is an occupational hazard leading to the development of respiratory symptoms and respiratory diseases. Bioaerosols from concentrated animal feeding operations are rich in bacteria and could carry bacterial extracellular vesicles (EVs) that could induce lung inflammation. It is not known if organic dust contains bacterial EVs and whether they modulate lung inflammation. Herein, we show that poultry organic dust contains bacterial EVs (dust EVs) that induce lung inflammation. Treatment of airway epithelial cells, THP-1-monocytes and -macrophages with dust EVs rapidly induced IL-8, IL-6, ICAM-1, proIL-1β, and TNF-α levels. In airway epithelial cells, induction of inflammatory mediators was due to increased mRNA levels and NF-κB activation. Induction of inflammatory mediators by dust EVs was not inhibited by polymyxin B. Single and repeated treatments of mice with dust EVs increased lung KC, IL-6, and TNF-α levels without significantly altering IL-17A levels. Increases in cytokines were associated with enhanced neutrophil infiltration into the lung. Repeated treatments of mice with dust EVs increased lung mean linear intercept and increased collagen deposition around airways indicating lung remodeling. Peribronchial cell infiltrates and airway epithelial thickening were also observed in treated mice. Because bacterial EVs are nanometer-sized particles, they can reach and accumulate in the bronchiolar and alveolar regions causing lung injury leading to the development of respiratory diseases. Our studies have provided new evidence for the presence of bacterial EVs in organic dust and for their role as one of the causative agents of organic dust-induced lung inflammation and lung injury.

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Novel AKT Activator SC79 Protects Airway Epithelial Cells Against Cadmium‐Induced Lung Injury

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.481.2 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Indiwari Gopallawa ◽

Robert J Lee

Keyword(s):

Epithelial Cells ◽

Lung Injury ◽

Airway Epithelial Cells ◽

Airway Epithelial

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Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells

European Respiratory Journal ◽

10.1183/13993003.03988-2020 ◽

2021 ◽

pp. 2003988

Author(s):

Kelly S. Schweitzer ◽

Taylor Crue ◽

Jordan M. Nall ◽

Daniel Foster ◽

Satria Sajuthi ◽

...

Keyword(s):

Epithelial Cells ◽

Lung Injury ◽

Influenza A ◽

Viral Infections ◽

Influenza Virus Infection ◽

Airway Epithelial Cells ◽

Small Airway ◽

Small Airways ◽

Airway Epithelial ◽

Small Airway Epithelial Cells

Patients with COVID-19 caused by severe acute respiratory syndrome coronavirus (SARS-Co-V)-2 demonstrate high rates of co-infection with respiratory viruses, including influenza A (IAV), suggesting pathogenic interactions. We investigated how IAV may increase the risk for COVID-19 lung disease, focusing on the receptor Angiotensin Convertase Enzyme 2 (ACE2) and the protease TMPRSS2, which cooperate to uptake SARS-CoV-2 intracellular. We found, using single cell RNA sequencing of distal human non-diseased lung homogenates, that at baseline, ACE2 is minimally expressed in basal, goblet, ciliated, and secretory epithelial cells populating small airways. We focused on human small airway epithelial cells (SAEC), central to the pathogenesis of lung injury following viral infections. Primary SAEC from non-diseased donor lungs apically infected (at air-liquid interface) with IAV (up to 3×105 pfu; ∼1 MOI) markedly (8-fold) boosted the expression of ACE2, paralleling that of STAT1, a transcription factor activated by viruses. IAV increased the apparent electrophoretic mobility of intrac¬ellular ACE2 and generated an ACE2 fragment (90 kDa) in apical secretions, suggesting cleavage of this receptor. IAV also increased the expression of two proteases known to cleave ACE2, sheddase ADAM17 (TACE) and TMPRSS2 and increased the TMPRSS2 zymogen and its mature fragments, implicating proteolytic autoactivation. These results indicate that IAV amplifies the expression of molecules necessary for SARS-CoV-2 infection of the distal lung. Further, posttranslational changes in ACE2 by IAV may increase the vulnerability to lung injury such as ARDS during viral co-infections. These findings support prevention and treatment efforts of influenza infections during the COVID-19 pandemic.

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Sodium Nitrite Enhances Lung Airway Epithelial Cells Wound Healing In Vitro And Alleviates LPS-induced Acute Lung Injury In Mice

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a3610 ◽

2010 ◽

Author(s):

LING WANG ◽

Bryan J. McVerry ◽

Sheila A. Frizzell ◽

Mark T. Gladwin

Keyword(s):

Wound Healing ◽

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Sodium Nitrite ◽

Airway Epithelial Cells ◽

Airway Epithelial

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Clusterin Deficiency Exacerbates Hyperoxia-Induced Acute Lung Injury

Cells ◽

10.3390/cells10040944 ◽

2021 ◽

Vol 10 (4) ◽

pp. 944

Author(s):

Jung Yeon Hong ◽

Mi Na Kim ◽

Eun Gyul Kim ◽

Jae Woo Lee ◽

Hye Rin Kim ◽

...

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Mortality Rate ◽

Epithelial Cells ◽

Lung Injury ◽

Intracellular Signaling ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Human Airway ◽

Human Airway Epithelial Cells

Exposure to high oxygen concentrations leads to generation of excessive reactive oxygen species, causing cellular injury and multiple organ dysfunctions and is associated with a high mortality rate. Clusterin (CLU) is a heterodimeric glycoprotein that mediates several intracellular signaling pathways, including cell death and inflammation. However, the role of CLU in the pathogenesis of hyperoxic acute lung injury (HALI) is unknown. Wild-type (WT) and CLU-deficient mice and cultured human airway epithelial cells were used. Changes in cell death- and inflammation-related molecules with or without hyperoxia exposure in cells and animals were determined. Hyperoxia induced an increase in CLU expression in mouse lungs and human airway epithelial cells. Mice lacking CLU had increased HALI and mortality rate compared with WT mice. In vitro, CLU-disrupted cells showed enhanced release of cytochrome c, Bax translocation, cell death and inflammatory cytokine expression. However, treatment with recombinant CLU attenuated hyperoxia-induced apoptosis. Moreover, the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses revealed metabolic pathways, hematopoietic cell lineage, response to stress and localization and regulation of immune system that were differentially regulated between WT and CLU−/− mice. These results demonstrate that prolonged hyperoxia-induced lung injury is associated with CLU expression and that CLU replenishment may alleviate hyperoxia-induced cell death.

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