Mimetic peptide AC2-26 of annexin A1 as a potential therapeutic agent to treat COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is related to inflammatory process caused by smoking habit. In this scenario, the anti-inflammatory protein Annexin A1 (AnxA1) may represent a therapeutic alternative. We performed experiments to evaluate the effects of the AnxA1 mimetic peptide Ac2-26 in an initial COPD model by physiological, histopathological, biochemical and immunohistochemical analyses. Weight loss, increased blood pressure, reductions in the pulmonary frequency and ventilation, loss of tracheal cilia, enlargement of the pulmonary intra-alveolar spaces and lymphoid tissue found in untreated smoke-exposed group were attenuated by AnxA1 peptide treatment. The Ac2-26 administration also protected against leukocytes influx in bronchoalveolar lavage (BAL), lung and trachea, and it also led to decreased hemoglobin, glucose, cholesterol, gamma glutamyl transferase and aspartato aminotransferase levels. Similarly, reduction of proinflammatory mediators and higher concentration of anti-inflammatory cytokine were found in macerated lung supernatant, blood plasma and BAL in the treated animals. Besides Ac2-26 group showed reduced tissue expressions of AnxA1, cyclooxygenase-2 and metalloproteinase-9, but formylated peptide receptor 2 (FPR2) overexpression. Our results all together highlighted the protective role of the Ac2-26 mimetic peptide in COPD with promising perspectives.

The role and mechanism of the annexin A1 peptide Ac2‐26 in rats with cardiopulmonary bypass lung injury

“…Experiments have confirmed that ANX‐A1 inhibits the adhesion of PMNs to endothelial cells by inducing L‐selectin detachment in neutrophils and simultaneously activates caspase‐3 to promote PMN apoptosis to regulate inflammation 32 . In a smoke‐induced rat lung inflammation model, the use of Ac2‐26 alleviated lung epithelial damage caused by smoke exposure 33 . In the IR‐induced ALI model, the use of Ac2‐26 significantly reduced lung neutrophil infiltration, improved lung injury scores and provided lung protection 34 .…”

“…There was no significant difference between the two groups. The reason may be that (a) the inflammation caused by lung IR was inhibited after adding Ac2‐26 33 ; (b) in the COPD model, 35 Lucas et al proposed that the reduction in endogenous ANX‐A1 after Ac2‐26 injection was associated with negative feedback regulation. (c) There are also studies 36 indicating that Ac2‐26 may regulate the conversion of endogenous ANX‐A1 between 37 and 34 kDa.…”

“…32 In a smoke-induced rat lung inflammation model, the use of Ac2-26 alleviated lung epithelial damage caused by smoke exposure. 33 In the IR-induced ALI model, the use of Ac2-26 significantly reduced lung neutrophil infiltration, improved lung injury scores and provided lung protection. 34 Studies have shown that under normal conditions, ANX-A1 is mainly inactive in the cytoplasm.…”

Therapeutic Potential of Annexins in Sepsis and COVID-19

“…Annexin A1 and its derivative peptides have been shown to have therapeutic effect in various disease states, including sepsis ( Gavins et al, 2012 ; Zhang et al, 2018 ), lung inflammation ( da Cunha et al, 2012 ) and chronic obstructive pulmonary disease (COPD) ( Possebon et al, 2018 ), myocardial infarction ( D’ Amico et al, 2000 ; La et al, 2001 ; Qin et al, 2015 ), and intestinal wound repair ( Babbin et al, 2008 ). Studies confirmed that endogenous annexin A1 plays a role in promoting phagocytosis ( Yona et al, 2006 ; Scannell et al, 2007 ), and its derived peptide Ac2-26 increases macrophage phagocytosis of apoptotic polymorphonuclear leukocytes (PMNs) ( Maderna et al, 2005 ).…”

“…Studies confirmed that endogenous annexin A1 plays a role in promoting phagocytosis ( Yona et al, 2006 ; Scannell et al, 2007 ), and its derived peptide Ac2-26 increases macrophage phagocytosis of apoptotic polymorphonuclear leukocytes (PMNs) ( Maderna et al, 2005 ). Ac2-26 administration in murine lipopolysaccharide (LPS) models of sepsis has demonstrated inhibition of cardiomyocyte apoptosis and myocardial damage ( Zhang et al, 2018 ), reduced leukocyte adhesion and cerebrovascular inflammatory response in the brain ( Gavins et al, 2012 ), and reduced inflammatory cytokine release and subsequent decreased inflammation in lung ( da Cunha et al, 2012 ; Possebon et al, 2018 ). Another annexin A1 analogue (CR-Ac 2-50 ) reduces inflammation and attenuates myocardial dysfunction in a polymicrobial sepsis model ( Dalli et al, 2013 ; Gobbetti et al, 2014 ).…”