Lung Macrophages in Health and Disease

Effective pulmonary host defense is orchestrated by complex interactions between pulmonary surfactant and alveolar macrophages. Pulmonary macrophages fulfill diverse roles in surveillance and inactivation of inhaled pathogens and in regulating surfactant homeostasis. Pulmonary surfactant proteins have innate protective activity and influence macrophage function. Mutations in genes that alter surfactant proteins, surfactant production or catabolism in the lung have been linked to human disease and are associated with abnormal macrophage function or alternative activation of pulmonary macrophages. Manipulation of the analogous genes in transgenic and gene targeted mice replicate aspects of macrophage related pulmonary disease. The genetic mouse models have been used to investigate the molecular pathogenesis and progression of acute and chronic lung disease of infancy, familial interstitial lung disease and pulmonary alveolar proteinosis.

Macrophages contribute to both initiation and resolution of inflammatory processes. These cells of diverse functional activity participate as both effectors and affectors in host tissue development, homeostasis and response to injury. Survival and function of the macrophage is dependent on colony stimulating factors granulocyte colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF). These colony stimulating factors play a significant role in defining the phenotype and activity of macrophages through regulating the expression of transcription factors PU.1 and peroxisome proliferator activator receptor gamma (PPARγ). Recent data suggests that alveolar macrophages are not passive participants in immune responses and that the status of “macrophage activation” defines the phenotype of the ensuing innate and adaptive responses. The status of alveolar macrophage activation, including cytokine production, phagocytosis, and antigen presentation, orchestrates the intensity and duration of the immune response. This chapter summarizes the perspectives of colony stimulating factor regulation of macrophage activity in immunity and pulmonary homeostasis.

Macrophages contribute significantly to the development and progression of chronic lung diseases and lung cancer [1-3]. Persistent stimulation by airborne irritants promotes recruitment of blood monocytes into the lung and also disrupts homeostatic control of interstitial and alveolar macrophages [1-3]. Both resident and recruited macrophages contribute to increased oxidative stress and to the production of inflammatory, fibrotic, and angiogenic cytokines that promote the hyperplasia and fibrosis of Chronic Obstructive Pulmonary Disease (COPD) as well as the growth and metastasis of lung tumors [1,2,4-13]. These studies raise several broad questions. Why do the functions of resident macrophages change? Alveolar macrophages function predominantly in particle clearance and are considered to have “restrained” inflammatory and cytotoxic activity [14,15]. The functional activities displayed by macrophages in COPD and lung cancer are very diverse, including production of both inflammatory and anti-inflammatory cytokines and expression of both tissue destructive (e.g., oxidants, metalloproteinases) and tissue reparative (e.g., angiogenic and growth factors) activities [1,2,4,5,7,8,13,16]. How are they converted to produce inflammatory mediators and matrix destructive proteinases [2,11-13]? How are these apparently antagonistic activities expressed simultaneously in diseased tissue? The following sections will provide insight into the answers to these questions, emphasizing the importance of tissue homeostatic mechanisms, microenvironmental influence on macrophage function, and macrophage functional plasticity. Macrophage biology will be discussed in the context of lung cancer, but given the similarities between macrophage contributions to cancer and COPD progression, the potential for therapeutic targeting of macrophage functional plasticity and tissue: macrophage interactions should apply to both diseases.

Apoptotic cell clearance is a vital process by which the body rids itself of unwanted cells, whether they become unwanted due to age, senescence, tissue remodeling and repair, or even damage. Efficient clearance of apoptotic cells depends upon the ability of the phagocyte to recognize and quickly engulf the effete cell before the apoptotic cells can progress to a state of secondary necrosis, spilling out phlogistic and possibly auto-immunogenic contents into the tissue. Removal of apoptotic cells in the lung by alveolar macrophages results in the maintenance of homeostasis, and alveolar macrophage recognition factors control process of clearance.

Repair of airway epithelial injury and resolution of inflammation are highly regulated processes. Inefficient clearance of apoptotic cells (efferocytosis) has the potential to cause an accumulation of apoptotic material and the subsequent development of secondary necrosis and perpetuation of chronic inflammation. Alveolar macrophages have the major role in effectively clearing excess apoptotic cells in the airway. Several studies have identified defective efferocytosis in the airways of subjects with chronic pulmonary diseases including chronic obstructive pulmonary disease (COPD), asthma, lung cancer and cystic fibrosis. These defects have been shown to at least partially relate to reduced levels of soluble mediators including mannose binding lectin (MBL) and collectins (surfactant proteins A and D), as well as dysregulated expression of various macrophage surface receptors and molecular pathways. These defects in macrophage function are potential targets for new therapeutic interventions for chronic lung diseases.

The increasing prevalence of inflammatory lung disease is becoming a major heath burden. Chronic inflammation is a key feature of asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. These patients are prone to bacterial pathogens that contribute to disease worsening. The reasons for this are unclear but may reflect defective pathogen clearance by alveolar macrophages. For example, alveolar macrophages from patients with COPD have a educed capacity to phagocytose bacteria and hence promote pulmonary bacterial colonisation. In cystic fibrosis macrophages are also defective in removing bacteria and this coupled with reduced acidification of the phagosome implies that macrophages contribute to ineffective bacterial uptake and subsequent killing. Bacteria can also employ diverse strategies to subvert the macrophage phagocytic pathway. For example, the capsule of Streptococcus pneumoniae prevents opsonisation by complement proteins and therefore is not removed efficiently by macrophages. Understanding the mechanisms underlying exacerbations of lung diseases will provide novel treatment strategies that will be of benefit for the patients in the short-term but could also prevent the acceleration of the disease process that is often associated with frequent exacerbations and ultimately improve the quality of life for patients already living with debilitating disease.

There is a growing body of evidence demonstrating that products of oxidative stress, namely carbonyl adducts, play a major role in chronic inflammation as well as age-related diseases. Their involvement crosses a broad spectrum of medical conditions encompassing airway diseases, such as asthma and COPD (chronic obstructive pulmonary disease) [1], neurodegenerative disorders like alzheimers [2], the cardiovascular disease atherosclerosis [3], and the arthritic diseases rheumatoid arthritis [4] and osteoarthritis [5]. Several good reviews exist highlighting the importance of carbonyl adducts in disease [6-8]. Not only do carbonyl adducts act as simple markers of tissue damage by oxidative stress, but they are able to participate in disease pathogenesis. This is accomplished through post-translational modification of protein, be it intra- or extra-cellular, the net effect being to alter cell function with the eventual tissue damage that follows [9-12].

Chronic alcohol abuse causes discrete changes in the alveolar macrophages that render the lung susceptible to serious infections such as tuberculosis. Many studies done in relevant animal models have identified common mechanisms by which alcohol abuse targets not only the alveolar macrophage but also the alveolar epithelium, thus resulting in lung injury. One of the mechanisms by which chronic alcohol ingestion results in oxidative stress is by decreasing the levels of the antioxidant glutathione within the alveolar space. Other studies have focused on depletion of essential micronutrients such as zinc that is also linked to oxidative stress mediated cellular dysfunction. These changes in the pulmonary microenvironment adversely affect granulocyte/ macrophage colony stimulating factor (GM-CSF) signaling in the alveolar macrophage, and thereby, dampens its function. Although the oxidative stress related changes are often subclinical and only lead to lung impairment when challenged by an acute insult such as trauma or sepsis, macrophage dysfunction at the cellular and the molecular levels is often evident in otherwise healthy alcoholics. In addition, chronic alcohol abuse increases the frequency and severity of ventilator-associated pneumonia, and increases susceptibility to viral infections such as HIV/AIDS. Thus, an understanding of the effects of chronic alcohol abuse on the function of alveolar macrophage has significant potential to identify new innovative treatments that could reduce the increased morbidity and mortality in this vulnerable population.

There is growing appreciation for the potential role of defective clearance of apoptotic cells by macrophages in disease pathogenesis. This has naturally lead to the consideration that therapies directed towards improving phagocytosis may have therapeutic utility. Some of these candidate therapies are already in use, although their initial rationale was for reasons other than improving phagocytosis. Examples are macrolide antibiotics, which are known to have antiinflammatory activities beyond their antimicrobial roles. In certain conditions (panbronchiolitis) these agents have become first-line therapy. Subsequent studies have revealed that at least part of their beneficial effects may be mediated via improvements in macrophage function. Statins and glucocortocosteroids also appear to act in part via improved phagocytosis. More recently, strategies are being pursued that are more specifically directed towards macrophage function, such as the use of mannose-binding lectin, but the initial rationale was to improve phagocytosis of microorganisms – the potential role in effercytosis has been realised subsequently. We have conducted a number of human and animal studies which support the potential role for improving phagocytosis as a therapeutic strategy for airways disease. A number of new strategies are emerging which show clinical promise.