BRD4 targeting nanotherapy prevents lipopolysaccharide induced acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is a life threatening respiratory disease associated with pulmonary edema, alveolar dysfunction, hypoxia, and inflammatory cell accumulation. The most contagious form of COVID-19 associated with ARDS caused by SARS-CoV-2. SARS-CoV-2 majorly produces the cytokine storm and severe lung inflammation and ultimately leads to respiratory failure. ARDS is a complex disease and there is no proper therapeutics for effective therapy. Still, there is a huge scope to identify novel targets to combat respiratory illness. In the current study, we have identified the epigenetic regulating protein BRD4 and developed siRNA based nanomedicine to treat the ARDS. The liposomes were prepared by thin-film hydration method, where BRD4 siRNA complexed with cationic lipid and exhibited 96.24 ± 18.01 nm size and stable even in the presence of RNase. BRD4 siRNA lipoplexes (BRD4-siRNA-LP) inhibited inflammatory cells in lungs and suppressed the lipopolysaccharide (LPS) induced the neutrophil infiltration and mast cell accumulation. Also, BRD4 siRNA based nanomedicine significantly reduced the LPS induced cytokine storm followed by inflammatory signaling pathways. Interestingly, BRD4-siRNA-LP suppressed the LPS-induced p65 and STAT3 nuclear translocation and ameliorated the lung inflammation. Thus, BRD4-siRNA-LP could be a plausible therapeutic option for treating ARDS and might be useful for combating the COVID-19 associated respiratory illness.

Green Tea Polyphenol Catechins Inhibit Coronavirus Replication and Potentiate the Adaptive Immunity and Autophagy-Dependent Protective Mechanism to Improve Acute Lung Injury in Mice

“…In the present study, the reasons for using a LPS model to develop ALI/ARDS can be used as a surrogate for virus induced ALI and cytokine storm as described below. Infections induced by influenza viruses, as well as COVID-19 pandemic induced by SARS-CoV-2 led to ALI and multiple organ failure [9,45], which could occur in LPS induced animal model. SARS-CoV-2 enters the cells through binding to ACE2, a protein highly expressed in the lungs and inhibition of ACE2 could result in the inflammatory bradykinin production in the lung [46].…”

“…Severe COVID-19 patients have displayed a high level of cytokine storm [20]. LPS-evoked sepsis induced ALI and cytokine storm may mimic these aspects of COVID-19 and SARS [9]. We thus determined the catechins effect on plasma IL-2 and IFN-γ secretion in the LPS-treated mice.…”

“…Cumulated reports evidenced that some patients with severe COVID-19 might display a syndrome with a distinct cytokine storm [5,6], reduction in CD8 + cell [7], and acute lung injury (ALI) associated with pulmonary inflammation and increased microvascular permeability [8]. SARS-CoV and SARS-CoV-2 could induce acute respiratory distress syndrome (ARDS), pulmonary inflammation, cytokine storm, and multiple organ failure, which is mimicked by lipopolysaccharide (LPS), a bacterial endotoxin present on the outer membrane of Gram-negative bacteria, evoked ARDS and cytokine storm [9], suggesting SARS-CoV-2 and LPS-induced ALI/ARDS and cytokine storm possibly through some similar pathways. Autophagy is a highly conserved biological process that occurs in eukaryotes and maintains cell homeostasis and viability by recycling and reusing energy through PI3K/AKT/mTOR signaling to regulate the autophagy-related proteins expression, such as Beclin-1/Atg5-Atg12/LC3-II [10].…”

Relevance of BET Family Proteins in SARS-CoV-2 Infection

“…Moreover, combined inhibition of BET and JAK proteins has been shown to efficiently reverse inflammation linked to bone marrow fibrosis [222]. Brd4 siRNA delivery through liposome nanoparticles efficiently suppresses RELA and STAT3 activation in LPS-induced mouse models of inflammation [223].…”

N-Acetylcysteine in Mechanically Ventilated Rats with Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: The Effect of Intravenous Dose on Oxidative Damage and Inflammation

“…Recruited and activated neutrophils also secret various toxic molecules, including oxygen free radicals, which can result in damage of capillary and alveolar endothelia [ 10 ]. In addition, LPS affects translocation of the transcription factors p65 NF-κB and signal transducer and activator of transcription 3 (STAT3) from the cytoplasm to the nucleus, triggering the transcription of several proinflammatory genes responsible for cytokine storm [ 11 ]. Therapeutic protocol for ARDS patients is based on lung-protective ventilation, fluid-restrictive strategies, and prone positioning, with emphasis on iatrogenic lung injury prevention [ 12 ].…”