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

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.

Utility of NO and H2S donating platforms in managing COVID-19: Rationale and promise

“…ARDS is characterized by diffuse alveolar damage and compromised gas exchange, lung stiffness, and edema [ 34 , 65 ], with patients experiencing shortness of breath and hypoxemia, many requiring mechanical ventilation (MV) [ 66 ]. Mortality rates among COVID-19 patients requiring invasive mechanical ventilation (IMV) are reportedly high, with an estimated overall fatality rate of 45% among 57,420 COVID-19 IMV cases from 69 studies [ 67 ].…”

“…The anti-inflammatory properties of NO are also promising for reducing ventilator-induced lung injury (VILI). In a model of shear-stress induced epithelial cells resembling VILI, pre-treatment with NO-releasing nanoparticles pre-and post-exposure reduced cell injury and cell death, with ROS and IL-6 levels significantly reduced [ 65 ]. These findings indicate a potential in severe COVID-19 cases to curtail excessive inflammation and ameliorate lung injury through MV.…”

The Potential Contribution of Biopolymeric Particles in Lung Tissue Regeneration of COVID-19 Patients

“…Finally, the levels of reactive ROS in each group were assessed. AFM studies showed that NO exposure alters cell shape before and after shear exposure, and qRT-PCR revealed a significant decrease in IL6 and CCL2 production when the cells were treated with NO through nanoparticles [46]. Statistical shape modeling was used to create four diseased lung models with different degrees of bronchial dilation and constriction in the left-lower lobe.…”

Advanced materials used in wearable health care devices and medical textiles in the battle against coronavirus (COVID-19): A review

“…The main areas of research include studying the transmission of COVID-19 and facilitating its detection, developing possible vaccines and treatments, and understanding the social and economic impacts of the pandemic. [1][2][3][4][5] Also researchers worldwide have been working to provide clothing and protective tools for doctors as well as the nursing staff to provide protection from disease transmission as well as providing comfort and flexibility for ease of work. [4][5][6] In addition to provide tools for patients for ease of household insulation, such as devices for measuring temperature, respiration and pressure.…”