Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice

Abstract

Sepsis is a life-threatening syndrome accompanied by an overwhelming inflammatory response and organ dysfunction. Selective targeting of phosphodiesterase 4 (PDE4) is currently being investigated as an effective therapeutic approach for inflammation-associated diseases. Roflumilast is a selective PDE4 inhibitor, used for the treatment of severe chronic obstructive pulmonary disease in clinic. However, its role in the treatment of sepsis-induced liver damage remains unclear. In the present study, we evaluated the effects of roflumilast in mice with cecal ligation and puncture-induced sepsis, and investigated the underlying mechanism. We found that roflumilast treatment improved survival in septic mice by reducing bacterial load locally and systemically, inhibiting the expression of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor alpha, and alleviating liver injury. These effects were associated with the inhibition of nuclear translocation of nuclear factor-kappa B (NF-κB), as well as degradation of NF-κB inhibitory protein alpha. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also markedly inhibited by roflumilast. Moreover, roflumilast significantly suppressed the activation of signal transducer and activator of transcription 3 (STAT3) and its upstream Janus kinase 1 and Janus kinase 2. Taken together, these results indicate that roflumilast prevents polymicrobial sepsis likely by suppressing NF-κB, p38 MAPK, and STAT3 pathways.

Role of cAMP and phosphodiesterase signaling in liver health and disease

“…Based on these observations, our group later identified the alcohol-mediated increase of PDE4B as a cause of diminished cAMP levels and an underlying mechanism of alcohol-mediated “priming”; PDE4 inhibition abrogates alcohol-mediated “priming” of monocytes/macrophages and production of high levels of TNFα [92]. Protective effect of PDE4 inhibitors, Rolipram and roflumilast, has also been demonstrated in various murine models of inflammation-driven liver injury [161–165]. Importantly, our recent study demonstrated that chronic alcohol feeding reduced hepatic cAMP leading to decreased phospho-CREB levels in a mouse ALD model [74].…”

Acetic acid alleviates the inflammatory response and liver injury in septic mice by increasing the expression of TRIM40

“…A number of studies investigated the involvement of NF-κB in sepsis-induced liver injury (40,41). Feng et al (46) demonstrated that the degradation of NF-κB inhibitor α (IκB-α) and the accumulation of NF-κB in the nucleus increased in septic mice, and roflumilast alleviated liver injury by inhibiting the expression of NF-κB and degradation of IκB-α. Those results suggested that NF-κB is closely associated with liver injury in septic mice and liver injury was ameliorated by inhibiting the expression of NF-κB.…”

New putative insights into Neprilysin (NEP)-dependent pharmacotherapeutic role of Roflumilast in treating COVID-19

“…The anti-inflammatory mechanisms of roflumilast can be contributed to its PDE4 inhibiting activity; leading to an increase in cAMP concentration and signaling within the epithelial airway and inflammatory cells. The action which in turn will enable roflumilast to suppress the expression of pro-inflammatory cytokines as IL-6 and TNF-α (Feng et al, 2017). Moreover, another study of cigarette smoke-induced pulmonary inflammation in guinea pigs showed that roflumilast could effectively reduce the numbers of neutrophils, lymphocytes and eosinophils in bronchoalveolar lavage fluid (Fitzgerald et al, 2006).…”

“…Among the released cytokines, IL-6 will play a vital role in the progression of numerous inflammatory reactions as well as endothelial dysfunction and platelets activation (Funakoshi et al, 1999;Liu et al, 2020c). Therefore, cleaving cathepsin G by NEP with reducing associated Ang II formation may be a logical commentary for the suppressed IL-6 expression detected following roflumilast treatment (Feng et al, 2017).…”