Azithromycin therapy reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction: Potential therapeutic targets in ischemic heart disease

Abstract

IntroductionAcute myocardial infarction (MI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-MI inflammation. Pro-inflammatory macrophages can lead to adverse cardiac remodeling and heart failure while anti-inflammatory/reparative macrophages enhance tissue healing. Shifting the balance between pro-inflammatory and reparative macrophages post-MI is a novel therapeutic strategy. Azithromycin (AZM), a commonly used macrolide antibiotic, polarizes macrophages towards the anti-inflammatory phenotype, as shown in animal and human studies. We hypothesized that AZM modulates post-MI inflammation and improves cardiac recovery.Methods and resultsMale WT mice (C57BL/6, 6–8 weeks old) were treated with either oral AZM (160 mg/kg/day) or vehicle (control) starting 3 days prior to MI and continued to day 7 post-MI. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory (CD45+/Ly6G-/F4-80+/CD86+) and increase in anti-inflammatory (CD45+/Ly6G-/F4-80+/CD206+) macrophages, decreasing the pro-inflammatory/anti-inflammatory macrophage ratio in the heart and peripheral blood as assessed by flow cytometry and immunohistochemistry. Macrophage changes were associated with a significant decline in pro- and increase in anti-inflammatory cytokines. Mechanistic studies confirmed the ability of AZM to shift macrophage response towards an anti-inflammatory state under hypoxia/reperfusion stress. Additionally, AZM treatment was associated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the anti-inflammatory phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis.ConclusionAzithromycin plays a cardioprotective role in the early phase post-MI through attenuating inflammation and enhancing cardiac recovery. Post-MI treatment and human translational studies are warranted to examine the therapeutic applications of AZM.

Biological responses following one‐stage full‐mouth scaling and root planing with and without azithromycin: Multicenter randomized trial

“…This result is also supported by previous studies that reported fewer patients with bacteremia among those who underwent SRP with oral AZM . The use of AZM also suppresses the production of cytokines, such as TNF‐α and IL‐6, which are involved in increasing body temperature, by dendritic cells . This may have inhibited the elevation of temperature in the experimental group.…”

“…Furthermore, in the gingival crevicular fluid sample of the experimental group, the levels of several factors (hs‐CRP, IL‐6, and TNF‐α) improved significantly at 6 weeks postoperatively compared with the baseline. There has been a report that AZM suppresses inflammatory cytokines and alleviates inflammation ; therefore, it may have some sort of effect in alleviating inflammation in the acute to recovery phases. This issue requires further investigation.…”

“…Mann-Whitney's U test was used for the statistical analysis for each group (*: P < 0.05) cytokines, such as TNF-α and IL-6, which are involved in increasing body temperature, by dendritic cells. 45,46 This may have inhibited the elevation of temperature in the experimental group.…”

Adult spiny mice (Acomys) exhibit endogenous cardiac recovery in response to myocardial infarction

“…Baseline cardiac function was assessed as previously described. 18 A heating pad and rectal temperature probe were utilized to keep body temperature at 37°C during the experiment. Modified parasternal long-axis and short-axis was utilized to determine left ventricular function and volume in M-mode, twodimensional and Doppler echocardiography modes.…”

“…Immunohistochemical assessments were carried out on deparaffinized and rehydrated sections as previously described. 18 After deparaffinization, washing, TRIS heat induced epitope retrieval, and protein and streptavidin/biotin blocking, slides were incubated with primary antibody: Isolectin B4 (L-2140, Sigma, St. Louis, MO) overnight at 4°C. After washing, sections were incubated with secondary antibody conjugated to streptavidin-Alexa Fluor 568 (S11226, Thermo Fisher Scientific, Waltham, MA) for 30 minutes, and cover slipped with mounting medium containing DAPI counterstain (Vector #H-1200).…”