Lung Remodeling in Pulmonary Tuberculosis
Centre for Infectious Diseases and International Health, Department of Thoracic and HIV Medicine, Royal Free Hospital
Department of Thoracic Medicine, Middlesex Hospital, Royal Free and University College Medical School, London, United Kingdom
Tuberculosis is a global public health catastrophe responsible for >8 million cases of illness and 2 million deaths annually. Pulmonary cavitation with cough-generated aerosol is the principle means of spread, and lung remodeling (healed cavitation, fibrosis, and bronchiectasis) is a major cause of lung disability, surpassing all other diffuse parenchymal lung diseases combined. Efficient granuloma turnover is mycobactericidal, and extracellular matrix is disbanded without scarring. In many with progressive disease, however, there is dysregulated granuloma turnover, liquefactive necrosis, and pathological scarring. The pathological mechanisms and the related immunological pathways underpinning these phenomena are reviewed in the present article. Further studies are needed to identify and develop specific immunotherapeutic interventions that target immunopathology, since they have the potential to substantially reduce spread.
The lung remodeling associated with pulmonary tuberculosis (TB) (healed cavitation, fibrosis, and distorted architecture) has never been satisfactorily explained. This is despite TB being an international public health priority and despite cavitation, with associated tissue and liquefactive necrosis, being the mechanism by which disease transmission occurs. In addition to addressing the significant morbidity associated with lung remodeling, investigations that can elucidate mechanisms and immunological pathways relevant to tissue necrosis might lead to strategies for interrupting aerosol-mediated transmission. Such knowledge can be incorporated into immunotherapeutic strategies aimed at halting person-to-person spread of Mycobacterium tuberculosis.
Why do caseous and liquefactive necrosis occur Moreover, why is fibrosis present in a disease characterized by a potent interferon (IFN) response, when this cytokine generally opposes fibrosis [1] In this review, we reevaluate current knowledge of the immunopathogenesis of tissue necrosis and fibrosis. Peer-reviewed data for the present article were identified by searches of the Medline and PubMed databases, up to and including October 2004, in all languages, by use of the search terms "tuberculosis" and "remodeling," "cavitation," "fibrosis," "immunopathology," "extracellular matrix," "protease," or "necrosis." Other sources were the references cited in retrieved articles and referenced textbooks.
DEFINITIONS
In asthma and chronic obstructive pulmonary disease, "remodeling" refers to anatomical and structural changes that are not easily reversible (laying down of extracellular matrix [ECM]), in contrast to reversible changes, such as edema and cellular infiltration) [2, 3]. In this review, we have extended the term "remodeling" to include residual cavitation, lung fibrosis or scarring, distortion of lung architecture leading to volume loss, and tuberculous bronchiectasis, all of which represent an inappropriate response to lung injury. An appropriate response occurs, for example, when granuloma formation occurs in a coordinated fashion, followed by disbanding of the granuloma, dissolution of ECM, and return to normal tissue architecture. "Fibrosis" implies a structural alteration, with laying down of collagenous ECM by fibroblasts and other cell types. The fibrosis may be interstitial; occur as a capsule around cavities; be bandlike, with distortion of the lung architecture; or be a combination of these. The term "tissue necrosis" encompasses both caseous and liquefactive necrosis.
CLINICAL ASPECTS
Cavitation into airways, with cough-induced aerosol generation, is the principle method by which TB is spread. Untreated, there is a fatal outcome in 50% of individuals [4]. Despite chemotherapy, however, there may be widespread lung destruction with significant associated mortality [5]. Alternatively, subsequent healing can result in extensive fibrosis, traction bronchiectasis [6, 7], and bronchostenosis [8], all of which may result in volume loss, a restrictive defect during pulmonary function testing [9, 10], and increased morbidity. Cavitation may erode blood vessels, and bronchiectasis may cause significant hemoptysis [8, 11]. Poor drug penetration into cavities and fibrocaseous foci, which are immunologically "sealed off," may facilitate latency and selection of drug resistance. Residual distortion of the lung architecture depends on the degree to which the connective-tissue matrix of a granuloma is degraded and removed. The key question is what determines whether a granuloma resolves completely without scarring or whether liquefactive necrosis and/or extensive scarring occurs.
EFFICIENT GRANULOMA FORMATION AND DISSOLUTION
The first cell types encountered by inhaled mycobacteria are the alveolar macrophages; phagocytosis is mediated by various host receptors [12, 13]. Lung T cells, NK T cells, and granulocytes are important early arrivals that precede the second wave of expanded, IFN- and tumor necrosis factor (TNF)producing effector T cell populations [1416]. Collectively, these cells initiate a chemokine and cytokine cascade that attracts other macrophages and, later, T cells to the site of infection [17] (figure 1). There is plasma exudation, and a fibrin clot is formed [18, 19]. Macrophage aggregation to form an early granuloma core is mediated by hyaluronic acid [20], which binds to macrophages via CD44 [21]. Detailed histological analyses of developing granulomata in the rabbit model [22] led to the view that macrophage activation driven by cell-mediated immunity is followed by destruction of the same macrophages, which then accumulate as caseous necrosis, and is often associated with death of the contained bacilli. An alternative view is that granulocytes are early arrivals that mediate the cell lysis that forms the core of developing caseous necrosis [16, 23, 24]. Recent pathological studies of granulomas in tuberculous human lungs indicate that the peripheral lymphocyte zones of the granuloma have secondary lymphoid follicles analogous to those found in lymph nodes [16].
Macrophages and other cell types, such as fibroblasts, endothelial cells, and neutrophils, also produce proteases (metalloproteinases [collagenase, gelatinase, and stromelysin]; the lysosomal proteinases [cathepsins]; and the plasminogen/plasmin system and its activator, urokinase]). Such enzymes may facilitate granuloma formation by mediating antigen processing, removal of ECM and cellular debris, and processing of cytokines and hormones [25]. They are tightly regulated at multiple levels, including transcription, proenzyme formation, and signaling control, as well as by tissue inhibitors
Department of Thoracic Medicine, Middlesex Hospital, Royal Free and University College Medical School, London, United Kingdom
Tuberculosis is a global public health catastrophe responsible for >8 million cases of illness and 2 million deaths annually. Pulmonary cavitation with cough-generated aerosol is the principle means of spread, and lung remodeling (healed cavitation, fibrosis, and bronchiectasis) is a major cause of lung disability, surpassing all other diffuse parenchymal lung diseases combined. Efficient granuloma turnover is mycobactericidal, and extracellular matrix is disbanded without scarring. In many with progressive disease, however, there is dysregulated granuloma turnover, liquefactive necrosis, and pathological scarring. The pathological mechanisms and the related immunological pathways underpinning these phenomena are reviewed in the present article. Further studies are needed to identify and develop specific immunotherapeutic interventions that target immunopathology, since they have the potential to substantially reduce spread.
The lung remodeling associated with pulmonary tuberculosis (TB) (healed cavitation, fibrosis, and distorted architecture) has never been satisfactorily explained. This is despite TB being an international public health priority and despite cavitation, with associated tissue and liquefactive necrosis, being the mechanism by which disease transmission occurs. In addition to addressing the significant morbidity associated with lung remodeling, investigations that can elucidate mechanisms and immunological pathways relevant to tissue necrosis might lead to strategies for interrupting aerosol-mediated transmission. Such knowledge can be incorporated into immunotherapeutic strategies aimed at halting person-to-person spread of Mycobacterium tuberculosis.
Why do caseous and liquefactive necrosis occur Moreover, why is fibrosis present in a disease characterized by a potent interferon (IFN) response, when this cytokine generally opposes fibrosis [1] In this review, we reevaluate current knowledge of the immunopathogenesis of tissue necrosis and fibrosis. Peer-reviewed data for the present article were identified by searches of the Medline and PubMed databases, up to and including October 2004, in all languages, by use of the search terms "tuberculosis" and "remodeling," "cavitation," "fibrosis," "immunopathology," "extracellular matrix," "protease," or "necrosis." Other sources were the references cited in retrieved articles and referenced textbooks.
DEFINITIONS
In asthma and chronic obstructive pulmonary disease, "remodeling" refers to anatomical and structural changes that are not easily reversible (laying down of extracellular matrix [ECM]), in contrast to reversible changes, such as edema and cellular infiltration) [2, 3]. In this review, we have extended the term "remodeling" to include residual cavitation, lung fibrosis or scarring, distortion of lung architecture leading to volume loss, and tuberculous bronchiectasis, all of which represent an inappropriate response to lung injury. An appropriate response occurs, for example, when granuloma formation occurs in a coordinated fashion, followed by disbanding of the granuloma, dissolution of ECM, and return to normal tissue architecture. "Fibrosis" implies a structural alteration, with laying down of collagenous ECM by fibroblasts and other cell types. The fibrosis may be interstitial; occur as a capsule around cavities; be bandlike, with distortion of the lung architecture; or be a combination of these. The term "tissue necrosis" encompasses both caseous and liquefactive necrosis.
CLINICAL ASPECTS
Cavitation into airways, with cough-induced aerosol generation, is the principle method by which TB is spread. Untreated, there is a fatal outcome in 50% of individuals [4]. Despite chemotherapy, however, there may be widespread lung destruction with significant associated mortality [5]. Alternatively, subsequent healing can result in extensive fibrosis, traction bronchiectasis [6, 7], and bronchostenosis [8], all of which may result in volume loss, a restrictive defect during pulmonary function testing [9, 10], and increased morbidity. Cavitation may erode blood vessels, and bronchiectasis may cause significant hemoptysis [8, 11]. Poor drug penetration into cavities and fibrocaseous foci, which are immunologically "sealed off," may facilitate latency and selection of drug resistance. Residual distortion of the lung architecture depends on the degree to which the connective-tissue matrix of a granuloma is degraded and removed. The key question is what determines whether a granuloma resolves completely without scarring or whether liquefactive necrosis and/or extensive scarring occurs.
EFFICIENT GRANULOMA FORMATION AND DISSOLUTION
The first cell types encountered by inhaled mycobacteria are the alveolar macrophages; phagocytosis is mediated by various host receptors [12, 13]. Lung T cells, NK T cells, and granulocytes are important early arrivals that precede the second wave of expanded, IFN- and tumor necrosis factor (TNF)producing effector T cell populations [1416]. Collectively, these cells initiate a chemokine and cytokine cascade that attracts other macrophages and, later, T cells to the site of infection [17] (figure 1). There is plasma exudation, and a fibrin clot is formed [18, 19]. Macrophage aggregation to form an early granuloma core is mediated by hyaluronic acid [20], which binds to macrophages via CD44 [21]. Detailed histological analyses of developing granulomata in the rabbit model [22] led to the view that macrophage activation driven by cell-mediated immunity is followed by destruction of the same macrophages, which then accumulate as caseous necrosis, and is often associated with death of the contained bacilli. An alternative view is that granulocytes are early arrivals that mediate the cell lysis that forms the core of developing caseous necrosis [16, 23, 24]. Recent pathological studies of granulomas in tuberculous human lungs indicate that the peripheral lymphocyte zones of the granuloma have secondary lymphoid follicles analogous to those found in lymph nodes [16].
Macrophages and other cell types, such as fibroblasts, endothelial cells, and neutrophils, also produce proteases (metalloproteinases [collagenase, gelatinase, and stromelysin]; the lysosomal proteinases [cathepsins]; and the plasminogen/plasmin system and its activator, urokinase]). Such enzymes may facilitate granuloma formation by mediating antigen processing, removal of ECM and cellular debris, and processing of cytokines and hormones [25]. They are tightly regulated at multiple levels, including transcription, proenzyme formation, and signaling control, as well as by tissue inhibitors