Proteasome InhibitionIn VivoPromotes Survival in a Lethal Murine Model of Severe Acute Respiratory Syndrome

Abstract

Ubiquitination is a critical regulator of the host immune response to viral infection, and many viruses, including coronaviruses, encode proteins that target the ubiquitination system. To explore the link between coronavirus infection and the ubiquitin system, we asked whether protein degradation by the 26S proteasome plays a role in severe coronavirus infections using a murine model of SARS-like pneumonitis induced by murine hepatitis virus strain 1 (MHV-1). In vitro, the pretreatment of peritoneal macrophages with inhibitors of the proteasome (pyrrolidine dithiocarbamate [

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

“…MG-132 administered in relatively large doses (4 mg/kg, repeated seven times) did not ameliorate tubulointerstitial fibrosis in rat unilateral ureteral obstruction [37]. Positive effects of MG-132, namely attenuation pneumonitis and cytokine gene expression in vivo by reducing coronavirus were observed [28].…”

“…In a low dose (0.1 mg/kg) MG-132 administered intraperitoneally once per day even for 2 or 8 weeks may effectively prevent cardiac remodelling and dysfunction in pressure-overloaded hearts without marked drug toxicity [29]. The effects of intraperitoneal injection of MG-132 was also studied on urinary [37], musculoskeletal [20,42], and respiratory systems [28]. The study revealed that MG-132 is not an adequate treatment to prevent endotoxin-induced diaphragmatic dysfunction [20,42] but partially prevents muscle atrophy associated with disuse [20].…”

“…MG-132 properties, such as antiproliferative, anti-inflammatory, and induction of heat shock proteins, also make it the most widely used in the clinical impact of proteasome inhibition on the course of many processes at the cellular and tissue level, as well as having a link with studies of new proteasome inhibitors [15]. Literature reports indicate that under experimental conditions, intraperitoneal administration of MG-132 may play a beneficial role in the prevention and therapy of inflammatory diseases such as acute pancreatitis [9,24,50], inflammatory bowel disease [19], severe acute respiratory syndrome [28], and intestinal damage caused by ischaemia/reperfusion [1,21], and also partially prevents muscle atrophy associated with disuse [20]. However, data obtained on animal models are very controversial.…”

What shall we do with the damaged proteins in lung disease? Ask the proteasome!

“…Thus, it is feasible that this type of immune response contributes to the initiation of epithelial dysfunction and repeated airway damage in virus-mediated exacerbations in asthma. As inhibition of the proteasome has been shown not only to attenuate virus replication in acute lung pneumonitis but also to affect antigenic peptide processing and subsequent cytotoxic T-cell-mediated lysis responses, this may add to the therapeutic potential of proteasome inhibitors in asthma [70,71]. Only recently, the rationale for therapeutic application of proteasome inhibitors in asthma has been extended to the idea of depleting immunoglobulin-secreting plasma cells.…”

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

“…Cyclosporine and FK506 have emerged as examples of such inhibitors (De Wilde et al, 2011;Pfefferle et al, 2011;CarbajoLozoya et al, 2012). Other host pathway proteinsthat are potential antiviral drug targets have been identified (Ma et al, 2010;Bhardwaj et al, 2012;Millet et al, 2012;Smith et al, 2012;Zhao et al, 2012).…”