Pharmacological options to treat these diseases are limited, as traditionally used drugs address only the major symptoms of inflammatory bowel diseases and fail to conduct patients to complete remission ( Duijvestein et al., 2018).
Patients suffer from diarrhea, anemia, fatigue and severe gut pain, among other symptoms, which become more intense during acute episodes, causing them to lose workdays and drastically reducing quality of life ( Xu et al., 2018).
In 2016 in the United States alone, the prevalence of both maladies combined was last reported to be of one for every 209 people, and incidence increases steadily each year ( Luther and Dave, 2020) also, the estimated loss of earnings due to IBDs were calculated as $31 billion in the same year ( Xu et al., 2018). Ulcerative colitis and Crohn's disease comprise inflammatory bowel diseases (IBDs), which are widespread and pose burdens to healthcare systems worldwide ( Mak et al., 2020). Thus, our data highlight AnxA1 as a crucial factor for the therapeutic actions of pioglitazone on IBDs. Finally, pioglitazone treatment increased extracellular signal-regulated kinase (ERK) phosphorylation in AnxA1-expressing RAW 264.7 macrophages, but not in AnxA1-knockdown macrophages. LPS-mediated increase of AnxA1 cleaving in RAW 264.7 macrophages was also attenuated by pioglitazone treatment. Cytokine secretion, reactive oxygen species generation and MMP-9 expression caused by lipopolysaccharide (LPS) treatment in AnxA1-expressing RAW 264.7 macrophages were reduced by pioglitazone treatment, effects not detected in AnxA1 knockdown macrophages. Metalloproteinase-9 (MMP-9) and inactive 33 kDa AnxA1 levels were increased in the colon of diseased WT mice, which were reduced by pioglitazone treatment. AnxA1 expression was increased in tissue sections of diseased WT mice, correlating positively with presence of CD68 + macrophages. Clinical and histological parameters were more severe for AnxA −/− than WT mice, and 10 mg/kg pioglitazone treatment attenuated disease parameters in WT mice only. Experimental colitis was evoked by 2% dextran sodium sulfate (DSS) in AnxA1 knockout (AnxA1 −/−) or wild type (WT) C57BL/6 mice. We here investigated whether effects of pioglitazone, a PPARγ ligand, rely on AnxA1 actions to modulate IBD inflammation.
Annexin A1 (AnxA1), a glucocorticoid-modulated anti-inflammatory protein, plays a key role on IBD control and is a potential biomarker of IBD progression. Use of peroxisome proliferator activated-receptor γ (PPARγ) ligands for IBD treatment, while promising, lacks solid evidences to ensure its efficacy. Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases (IBDs) which burden health systems worldwide available pharmacological therapies are limited and cost-intensive. Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.Gustavo Henrique Oliveira da Rocha, Marina de Paula-Silva, Milena Fronza Broering, Pablo Rhasan dos Santos Scharf, Larissa Satiko Alcântara Sekimoto Matsuyama, Silvya Stuchi Maria-Engler and Sandra Helena Poliselli Farsky*