Fourteen-Member Macrolides Promote the Phosphatidylserine Receptor-Dependent Phagocytosis of Apoptotic Neutrophils by Alveolar Macrophages

Abstract

An inflammation of the airway of patients with diffuse panbronchiolitis (DPB), is characterized by dense neutrophil infiltration. Resolution of the inflammation can be achieved by the removal of apoptotic neutrophils by human alveolar macrophages (AM) without liberating neutrophil proteases in the airway. To understand clinical efficacy for the treatment of DPB by 14-or 15-member macrolides, their effects on the phagocytosis of apoptotic neutrophils by AM were examined. Treatment of AM with erythromycin (ERY) or clarithromycin at clinically achievable levels significantly increased the levels of phagocytosis of apoptotic neutrophils. A serum factor was not essential for the enhancement by these 14-member macrolides. Of the antibiotics tested, these effects were specific for the 14-member macrolides and a 15-member macrolide, azithromycin, but not for the 16-member macrolides, clindamycin or ␤-lactam antibiotics. The enhanced phagocytosis of apoptotic neutrophils by ERY had no effect on the levels of interleukin-8 or tumor necrosis factor alpha production by lipopolysaccharide-stimulated AM after phagocytosis of the apoptotic neutrophils. The increased phagocytosis of apoptotic neutrophils by ERY was also found to be phosphatidylserine receptor-dependent for AM. These data indicate a novel anti-inflammatory action of 14-member and 15-member macrolides, and suggest that such antibiotics achieve clinical efficacy for patients with DPB, in part, through enhancing the nonphlogistic phagocytosis of apoptotic neutrophils by AM.

Effect of cirrhosis on antibiotic efficacy in a rat model of pneumococcal pneumonia

“…Macrolides, including azithromycin, possess anti-inflammatory properties that could reduce the overall number of neutrophils in the respiratory tract (Yamaryo et al, 2003;Tamaoki, 2004). The macrolide anti-inflammatory response is generally thought to effect cytokine production and neutrophil accumulation in noninfected patients and animal models (Tamaoki, 2004).…”

Rokitamycin Induces a Mitochondrial Defect and Caspase-Dependent Apoptosis in Human T-Cell Leukemia Jurkat Cells

“…Recent studies suggest that a direct immunomodulating role of macrolides can be assumed as follows: neutrophil chemotaxis inhibition (15 -18), oxidant generation (15,19,20), phagocytosis progression (21,22), and apoptosis induction (23).…”

Pulmonary Macrophage-Targeted Therapies-The Way Forward in Chronic Inflammatory Lung Diseases?

“…In a small uncontrolled study using lowdose azithromycin in COPD subjects the principal findings were a significant increase in the efferocytosis capacity of alveolar macrophages and a reduction in the percentage of apoptotic airway epithelial cells obtained by airway brushing [7]. A role for phosphatidyserine (PS) in these effects was shown [8].…”

“…The mechanism of action of macrolides in this regard may be through their effects on macrophage function [6][7][8]. In a small uncontrolled study using lowdose azithromycin in COPD subjects the principal findings were a significant increase in the efferocytosis capacity of alveolar macrophages and a reduction in the percentage of apoptotic airway epithelial cells obtained by airway brushing [7].…”

“…The emerging body of evidence suggests that that the use of longterm macrolide therapy is both feasible and may offer useful clinical outcomes in chronic lung diseases, including COPD, BOS and NEA [6][7][8], while results in CF have been inconclusive [9,10]. The mechanism of action of macrolides in this regard may be through their effects on macrophage function [6][7][8].…”