Chest
Volume 140, Issue 3, September 2011, Pages 768-774
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Translating Basic Research into Clinical Practice
Alternatively Activated Macrophages and Airway Disease

https://doi.org/10.1378/chest.10-2132Get rights and content

Macrophages are the most abundant immune cell population in normal lung tissue and serve critical roles in innate and adaptive immune responses as well as the development of inflammatory airway disease. Studies in a mouse model of chronic obstructive lung disease and translational studies of humans with asthma and COPD have shown that a special subset of macrophages is required for disease progression. This subset is activated by an alternative pathway that depends on production of IL-4 and IL-13, in contrast to the classic pathway driven by interferon-γ. Recent and unexpected results indicate that alternatively activated macrophages (AAMs) can also become a major source of IL-13 production and, thereby, drive the increased mucus production and airway hyperreactivity that is characteristic of airway disease. Although the normal and abnormal functions of AAMs are still being defined, it is already apparent that markers of this immune cell subset can be useful to guide stratification and treatment of patients with chronic airway diseases. Here, we review basic and clinical research studies that highlight the importance of AAMs in the pathogenesis of asthma, COPD, and other chronic airway diseases.

Section snippets

AAMs in Mouse Models of Lung Disease

One of the first lines of evidence that AAMs contribute to chronic inflammatory disease of any kind comes from a mouse model of chronic airway disease that develops after an infection with a common type of respiratory virus.4 In this model, infection with mouse parainfluenza virus or Sendai virus leads to acute bronchiolitis followed by chronic airway disease that appears to mimic the sequence of events found in childhood asthma after infection with closely related human pathogens, such as

AAMs in Human Lung Disease

Macrophages are implicated in the development of airway inflammation and mucus production as well as the alveolar destruction that are all characteristic of COPD. Studies of mouse models and humans with COPD support a role for M1 macrophages in alveolar destruction as a basis for pulmonary emphysema.25 One study indicated that the pattern of gene expression in alveolar macrophages from smokers showed at least some overlap with genes found in mouse models of COPD, and this overlap included genes

AAM Biomarkers in Airway Disease

To the extent that AAMs drive chronic airway disease, they also offer an opportunity to monitor and stratify patients and thereby personalize diagnosis and treatment. Toward that end, an effort is being made to compile markers of AAM levels and/or activity that could be validated in experimental models and applied to patients with chronic obstructive lung disease. Two major challenges in this approach are the difficulties in predicting human orthologs of mouse genes and verifying that either

Future Directions

In this brief review, we highlight evidence that AAMs contribute to the pathogenesis of chronic airway diseases. This disease mechanism is supported by evidence from experimental models of postviral airway disease and translational studies of asthma and COPD in humans. In both cases, ongoing work needs to further define the basis for AAM activation as a means to better understand pathogenesis. Even at this stage of understanding, investigators have begun to develop clinical biomarkers of AAM

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Holtzman is the principal investigator of research grants from the National Institutes of Health, Hoffmann-La Roche Inc, and Forest Institute Inc to Washington University and has received honorariums for talks at other universities from Merck. Dr Byers has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed

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    Funding/Support: The research reviewed here was supported by grants from the National Institutes of Health (National Heart, Lung, and Blood Institute and National Institute of Allergy and Infectious Diseases) and the Martin Schaeffer Fund.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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