Nitric Oxide Releasing Hydrogel Nanoparticles Decreases Epithelial Cell Injuries Associated With Airway Reopening

Samar Shurbaji; Ibrahim M El-Sherbiny; Maha Alser; Isra H Ali; Haya Kordi; Ameena Al-Sadi; Anton Popelka; Fatiha Benslimane; Magdi Yacoub; Huseyin C Yalcin

doi:10.3389/fbioe.2020.579788

Nitric Oxide Releasing Hydrogel Nanoparticles Decreases Epithelial Cell Injuries Associated With Airway Reopening

Front Bioeng Biotechnol. 2021 Jan 5:8:579788. doi: 10.3389/fbioe.2020.579788. eCollection 2020.

Authors

Samar Shurbaji¹, Ibrahim M El-Sherbiny², Maha Alser¹, Isra H Ali², Haya Kordi^{1

3}, Ameena Al-Sadi^{1

3}, Anton Popelka⁴, Fatiha Benslimane¹, Magdi Yacoub⁵, Huseyin C Yalcin^{1

3}

Affiliations

¹ Biomedical Research Center, Qatar University, Doha, Qatar.
² Nanomedicine Lab, Center of Materials Sciences, Zewail City of Science and Technology, Giza, Egypt.
³ Department of Biomedical Sciences, College of Health Science-QU Health, Qatar University, Doha, Qatar.
⁴ Center for Advanced Materials, Qatar University, Doha, Qatar.
⁵ Heart Science Centre, Imperial College, National Heart and Lung Institute, London, United Kingdom.

Abstract

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung condition. It is characterized by disruption of gas exchange inside the alveoli, accumulation of protein edema, and an increase in lung stiffness. One major cause of ARDS is a lung infection, such as SARS-COV-2 infection. Lungs of ARDS patients need to be mechanically ventilated for airway reopening. Consequently, ventilation might damage delicate lung tissue leading to excess edema, known as ventilator-induced lung injury (VILI). Mortality of COVID-19 patients under VILI seems to be higher than non-COVID patients, necessitating effective preventative therapies. VILI occurs when small air bubbles form in the alveoli, injuring epithelial cells (EPC) due to shear stress. Nitric oxide (NO) inhalation was suggested as a therapy for ARDS, however, it was shown that it is not effective because of the extremely short half-life of NO. In this study, NO-releasing nanoparticles were produced and tested in an in vitro model, representing airways in the deep lung. Cellular injuries were quantified via fluorescent live/dead assay. Atomic force microscopy (AFM) was used to assess cell morphology. qRT-PCR was performed to assess the expression of inflammatory markers, specifically IL6 and CCL2. ELISA was performed to assess IL6 and confirm qRT-PCR results at the protein level. Finally, ROS levels were assessed in all groups. Here, we show that NO delivery via nanoparticles enhanced EPC survival and recovery, AFM measurements revealed that NO exposure affect cell morphology, while qRT-PCR demonstrated a significant downregulation in IL6 and CCL2 expression when treating the cells to NO both before and after shear exposure. ELISA results for IL6 confirmed qRT-PCR data. ROS experiment results support our findings from previous experiments. These findings demonstrate that NO-releasing nanoparticles can be used as an effective delivery approach of NO to deep lung to prevent/reduce ARDS associated inflammation and cell injuries. This information is particularly useful to treat severe ARDS due to COVID-19 infection. These nanoparticles will be useful when clinically administrated to COVID-19 patients to reduce the symptoms originating from lung distress.

Keywords: COVID-19; SARS-CoV-2; acute respiratory distress syndrome; hydrogel nanoparticle; mechanical ventilation; nitric oxide.