Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation

Abstract

Alveolar macrophages and BDMCs undergo sequential biochemical changes during the chronic inflammatory response to chemically induced lung carcinogenesis in mice. Herein, we examine two chronic lung inflammation models-repeated exposure to BHT and infection with Mycobacterium tuberculosis-to establish whether similar macrophage phenotype changes occur in non-neoplastic pulmonary disease. Exposure to BHT or M. tuberculosis results in pulmonary inflammation characterized by an influx of macrophages, followed by systemic effects on the BM and other organs. In both models, pulmonary IFN-gamma and IL-4 production coincided with altered polarization of alveolar macrophages. Soon after BHT administration or M. tuberculosis infection, IFN-gamma content in BALF increased, and BAL macrophages became classically (M1) polarized, as characterized by increased expression of iNOS. As inflammation progressed in both models, the amount of BALF IFN-gamma content and BAL macrophage iNOS expression decreased, and BALF IL-4 content and macrophage arginase I expression rose, indicating alternative/M2 polarization. Macrophages present in M. tuberculosis-induced granulomas remained M1-polarized, implying that these two pulmonary macrophage populations, alveolar and granuloma-associated, are exposed to different activating cytokines. BDMCs from BHT-treated mice displayed polarization profiles similar to alveolar macrophages, but BDMCs in M. tuberculosis-infected mice did not become polarized. Thus, only alveolar macrophages in these two models of chronic lung disease exhibit a similar progression of polarization changes; polarization of BDMCs was specific to BHT-induced pulmonary inflammation, and polarization of granuloma macrophages was specific to the M. tuberculosis infection.

Janus-faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection

“…M1 and M2 macrophages have been previously described as proinflammatory and antiinflammatory macrophages (29,30), respectively, playing different roles during chronic inflammatory pathologies, such as TB (31). Here, we show that stimulation with ABL/PA determines a significant increase in the killing of intracellular MTB by both types of macrophages (Fig.…”

Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology

“…Infection with more virulent M. tuberculosis strains (such as the W-Beijing strain HN878 used in this study) leads to greater IL-4 production than infections with less virulent strains in vitro 48 and in vivo. 49,50 IL-8 (CXCL8) recruits neutrophils to the site of infection in M. tuberculosis infected guinea pigs 34 and is elevated in bronchoalveolar lavage fluids from TB patients. 33,51,52 CRP is often routinely monitored as a clinical marker of inflammation.…”

Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis

“…Young mice (8 -10 wk) and aged mice (52-54 wk) were housed on hardwood bedding with 12:12-h light-dark cycles and fed standard rodent diet at the Center for Laboratory Animal Care at National Jewish Health. Mice were anesthetized by intraperitoneal injection of ketamine/ xylazine and subsequently administered bleomycin (3 U/kg, TEVA Pharmaceuticals, North Wales, PA) in 50 l of sterile saline or 50 l of saline alone as a control by intratracheal instillation following direct visualization of the trachea with a mouse laryngoscope (Penn-Century, Wyndmoor, PA), as described (18,45). Aged mice were dosed with the same amount of bleomycin as young mice, because, while their body mass increases with age, their lung volume remains stable once mature (Fig.…”