Azithromycin alters macrophage phenotype and pulmonary compartmentalization during lung infection with Pseudomonas.
Infection with mucoid strains of Pseudomonas aeruginosa in chronic inflammatory diseases of the airway is difficult to eradicate and can cause excessive inflammation. The roles of alternatively activated and regulatory subsets of macrophages in this pathophysiological process are not well characterized. We previously demonstrated that azithromycin induces an alternatively activated macrophage-like phenotype in vitro. In the present study, we tested whether azithromycin affects the macrophage activation status and migration in the lungs of P. aeruginosa-infected mice. C57BL/6 mice received daily doses of oral azithromycin and were infected intratracheally with a mucoid strain of P. aeruginosa. The properties of macrophage activation, immune cell infiltration, and markers of pulmonary inflammation in the lung interstitial and alveolar compartments were evaluated postinfection. Markers of alternative macrophage activation were induced by azithromycin treatment, including the surface expression of the mannose receptor, the upregulation of arginase 1, and a decrease in the production of proinflammatory cytokines. Additionally, azithromycin increased the number of CD11b(+) monocytes and CD4(+) T cells that infiltrated the alveolar compartment. A predominant subset of CD11b(+) cells was Gr-1 positive (Gr-1(+)), indicative of a subset of cells that has been shown to be immunoregulatory. These differences corresponded to decreases in neutrophil influx into the lung parenchyma and alteration of the characteristics of peribronchiolar inflammation without any change in the clearance of the organism. These results suggest that the immunomodulatory effects of azithromycin are associated with the induction of alternative and regulatory macrophage activation characteristics and alteration of cellular compartmentalization during infection.
Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY 43536-0082, USA. djfeol2@email.uky.edu
David J
DJ
Feola
Beth A
BA
Garvy
Theodore J
TJ
Cory
Susan E
SE
Birket
Heather
H
Hoy
Don
D
Hayes
Brian S
BS
Murphy
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010641:Phenotype; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011550:Pseudomonas aeruginosa
D000900:Anti-Bacterial Agents; D039481:CD11b Antigen; D039521:CD11c Antigen; D016207:Cytokines; D017963:Azithromycin