Andrew Churg

Animal models of chronic obstructive pulmonary disease

The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role.

The separation of benign and malignant mesothelial proliferations

The separation of benign from malignant mesothelial proliferations has emerged as a major problem in the pathology of the serosal membranes. For both epithelial and spindle cell mesothelial processes, true stromal invasion is the most accurate indicator of malignancy, but stromal invasion is often difficult to assess, especially in small biopsies. In the pleural cavity, deep penetration of a thickened and fibrotic pleura or penetration of mesothelial cells into the fat of the chest wall are good indicators of malignancy; however, superficial entrapment of mesothelial cells and glands by organizing effusions is common in benign reactions and needs to be distinguished from invasion. In the peritoneal cavity, invasion of fat or of organ walls is again the most reliable indicator of malignancy, but entrapment of benign cells in organizing granulation tissue or between fat lobules is frequent and confusing. Proliferations confined to the pleural or peritoneal space, particularly linear arrays of atypical mesothelial cells on the free surface, should not be called malignant in the absence of unequivocal invasion. Cytologic atypia is often not helpful in separating benign from malignant reactions, because benign processes are commonly atypical and mesotheliomas are often deceptively monotonous. Densely packed mesothelial cells within the pleural space are frequent in benign reactions, but densely packed mesothelial cells within the stroma favor a diagnosis of malignancy. Organizing effusions (fibrous pleurisy) typically show zonation with high cellularity and cytologic atypia toward the pleural space and increasing fibrosis with decreasing cellularity and lesser atypia toward the chest wall, whereas sarcomatous (including desmoplastic) mesotheliomas do not demonstrate this type of zonation. Elongated capillaries perpendicular to the pleural surface are seen in organizing effusions but are not a feature of sarcomatous mesotheliomas. The combination of a paucicellular storiform pattern, plus invasion of the stroma (including fat and adjacent tissues), or bland necrosis, overtly sarcomatous foci, or distant metastases, is required for the diagnosis of desmoplastic mesothelioma. Necrosis is usually a sign of malignancy but is occasionally seen in benign mesothelial reactions. Keratin staining is useful in indicating the distribution of mesothelial cells, and particularly in demonstrating penetration of mesothelial cells into the stroma or adjacent structures, but is of no help in separating benign and malignant proliferations because both are keratin-positive. Although both p53 and EMA staining have been proposed as markers of mesothelial malignancy, in our experience they are not helpful for the individual case.

Mechanisms of cigarette smoke-induced COPD: insights from animal models.

Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.

Myofibroblasts and related cells in malignant fibrous and fibrohistiocytic tumors.

Myofibroblasts were detected by electron microscopy in five of five cases of fibrosarcoma and in five of six cases of malignant fibrous histiocytoma. In some areas myofibroblasts constituted up to 75 per cent of the tumor cells. Most myofibroblasts contained only sheaves of myofilaments along the margins of the cells, but some cells contained larger bundles of myofilaments and very closely resembled smooth muscle cells. An additional related type of cell was seen in several cases; it was large and possessed abundant eosinophilic cytoplasm, resembling a rhabdomyoblast at the light microscopic level. By electron microscopy this type of cell was seen to contain plentiful rough endoplasmic reticulum and large aggregates of fine filaments with rare dense bodies. These findings suggest that fibrosarcomas and malignant fibrous histiocytomas contain cells showing a spectrum of differentiation from fibrocytic to myogenic and that at the ultrastructural level the distinction between fibroblast and smooth muscle tumors may be blurred.

Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs

Background: Matrix metalloproteases (MMPs) are believed to be important in the pathogenesis of cigarette smoke-induced emphysema, but this hypothesis has only been proved in the mouse and its applicability to other species, particularly humans, is uncertain. The role of MMPs in smoke-induced small airway remodelling is unknown. Methods: The effects of a dual MMP-9/MMP-12 inhibitor, AZ11557272, on the development of anatomical and functional changes of chronic obstructive pulmonary disease (COPD) in guinea pigs exposed daily to cigarette smoke for up to 6 months were examined. Results: At all times, smoke-induced increases in lavage inflammatory cells, lavage desmosine (a marker of elastin breakdown) and serum tumour necrosis factor α (TNFα) were completely abolished by AZ11557272. At 6 months there was an increase in lung volumes and airspace size. AZ11557272 returned the pressure- volume curve to control levels, decreased smoke-induced increases in total lung capacity, residual volume and vital capacity by about 70%, and also reversed smoke-induced airspace enlargement by about 70%. There was a very strong correlation between surface to volume ratio and both lavage desmosine and serum TNFα levels. AZ11557272 protected against smoke-mediated increases in small airway wall thickness but did not prevent smoke-induced increases in mean pulmonary artery pressure. Conclusions: An MMP-9/MMP-12 inhibitor can substantially ameliorate morphological emphysema, small airway remodelling and the functional consequences of these lesions in a non-murine species. These findings strengthen the idea that MMPs are important mediators of the anatomical changes behind COPD in humans, and suggest that MMP-9 and MMP-12 may be potential intervention targets.

Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias

Acute exacerbation of usual interstitial pneumonia (UIP) is a condition in which patients with UIP, and occasionally other forms of fibrotic interstitial lung disease, develop rapid respiratory failure, accompanied by extensive radiologic infiltrates. The pathologic features of this condition are ill-defined in the literature and the outcome is unclear. We report 12 such patients, 9 with underlying UIP, 2 with underlying fibrotic nonspecific interstitial pneumonia, and 1 with underlying chronic hypersensitivity pneumonitis, who underwent surgical lung biopsy for diagnosis. High-resolution computed tomography data were available in 11 cases and showed the presence of extensive bilateral ground-glass opacities, sometimes accompanied by focal consolidation, superimposed on underlying fibrosis. Three microscopic patterns of acute lung injury were seen: diffuse alveolar damage (DAD), organizing pneumonia (OP), and a pattern of numerous very large fibroblast foci superimposed on underlying fibrosis. After the biopsy, all patients were treated with steroids, in some instances accompanied by cyclophosphamide or azathioprine. Ten patients survived the acute episode and were discharged with survival times of 1 to 11 months; of these cases, 6 showed a pattern of OP or OP plus extensive fibroblast foci; 2 a pattern of extensive fibroblast foci only; and 2 a pattern of DAD. Both patients who died had histologic DAD. We conclude that acute exacerbation of UIP and other fibrotic lung diseases produces a variety of pathologic patterns on biopsy, and that patients with OP or extensive fibroblast foci as the acute pattern seem to do better than those with DAD. Our data also imply that survival (of the acute episode) may be better than the literature suggests.

Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment

The development of pulmonary hypertension is a poor prognostic sign in patients with chronic obstructive pulmonary disease (COPD), affecting both mortality and quality of life. Although pulmonary hypertension in COPD is traditionally viewed as a result of emphysematous destruction of the vascular bed and/or hypoxia, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressures. New human and animal experimental data are beginning to show that pulmonary hypertension in this setting is probably a result of the direct effect of tobacco smoke on the intrapulmonary vessels with abnormal production of mediators that control vasoconstriction, vasodilatation, and vascular cell proliferation, ultimately leading to aberrant vascular remodelling and aberrant vascular physiology. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest that the treatments used for primary pulmonary hypertension may be beneficial in patients with COPD.

Hypersensitivity Pneumonitis: Spectrum of High-Resolution CT and Pathologic Findings

OBJECTIVE The purpose of this article is to illustrate the spectrum of pathologic and high-resolution CT features of hypersensitivity pneumonitis (HP). CONCLUSION High-resolution CT plays an important role in the diagnosis of HP. A confident diagnosis of subacute HP is based on the presence of ground-glass opacities, poorly defined centrilobular nodules, and mosaic attenuation on inspiratory images and of air trapping on expiratory CT images. Chronic HP is characterized on high-resolution CT by the presence of reticulation due to fibrosis superimposed on findings of subacute HP. Histologically, subacute HP is characterized by the presence of cellular bronchiolitis, noncaseating granulomas, and bronchiolocentric lymphocytic interstitial pneumonitis. Areas of organizing pneumonia also may be seen. The high-resolution CT and pathologic features of chronic HP frequently overlap with those of nonspecific interstitial pneumonia and usual interstitial pneumonia. Awareness of the various manifestations of HP is important for early diagnosis and management.

The Role of Interleukin-1β in Murine Cigarette Smoke–Induced Emphysema and Small Airway Remodeling

Interleukin-1beta (IL-1beta), a proinflammatory cytokine, is elevated in cigarette smokers. To determine whether IL-1beta plays a role in the pathogenesis of cigarette smoke-induced emphysema and small airway remodeling, IL-1 receptor knockout (IL1RKO), TNF-alpha receptor knockout (TNFRKO), or C57Bl/6 (control) mice were exposed to cigarette smoke acutely or for up to 6 months. With a single acute exposure, smoke elevated IL-1beta in C57Bl/6 mice. IL1RKO mice were protected against acute smoke-mediated increases in lavage inflammatory cells and matrix breakdown. In C57Bl/6 mice, acute smoke-mediated increases in inflammatory cells, serum IL-1beta, and serum TNF-alpha were blocked by z-VAD-fmk, a pan-caspase inhibitor, or z-WEHD-fmk, a caspase-1 (IL-1-converting enzyme, [ICE]) inhibitor. With 6 months of exposure, IL-1beta was no longer increased, but IL-18 was elevated. After 6 months of exposure, IL1RKO mice were 65% protected against emphysema, whereas TNFRKO mice were 83% protected. Both strains were completely protected against small airway remodeling. Lavage desmosine, hydroxyproline, and hyaluronan, matrix breakdown markers, were elevated in C57 but not IL1RKO mice. We conclude that IL-1beta plays a significant role in induction of murine emphysema and small airway remodeling, and is comparable to TNF-alpha in its effects. The protective effects of caspase inhibitors appear to be related to inhibition of ICE and raise the question of whether models that ameliorate emphysema with caspase inhibitors are really blocking IL-1beta (and IL-18) activation rather than blocking apoptosis.

Chronic hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is traditionally divided on clinical grounds into acute, subacute, and chronic stages. Most biopsy specimens come from patients in the subacute stage, in which there is a relatively mild, usually peribronchiolar, chronic interstitial inflammatory infiltrate, accompanied in most cases by poorly formed interstitial granulomas or isolated giant cells. However, the pathologic features in the chronic, ie, fibrotic stage, are poorly defined in the literature. These features are important to recognize because the chronic stage of HP is often associated with a poor prognosis. We reviewed 13 cases of chronic HP. Where information was available, exposures to the sensitizing agent had generally occurred over a long period of time. Three patterns of fibrosis were seen: 1) predominantly peripheral fibrosis in a patchy pattern with architectural distortion and fibroblast foci resembling, microscopically, usual interstitial pneumonia (UIP); 2) relatively homogeneous linear fibrosis resembling fibrotic nonspecific interstitial pneumonia (NSIP); and 3) irregular predominantly peribronchiolar fibrosis. In some instances, mixtures of the UIP-like and peribronchiolar patterns were found. In all cases, the presence of scattered poorly formed granulomas, or isolated interstitial giant cells, or sometimes only Schaumann bodies indicated the correct diagnosis. In 7 cases, areas of typical subacute HP were present as well. High-resolution CT scans showed variable patterns ranging from severe fibrosis, in some instances with an upper zone predominance, to predominantly ground glass opacities with peripheral reticulation. We conclude that, at the level of morphology, chronic HP may closely mimic UIP or fibrotic NSIP. If no areas of subacute HP are evident, the presence of isolated giant cells, poorly formed granulomas, or Schaumann bodies is crucial to arriving at the correct diagnosis, and the finding of peribronchiolar fibrosis may be helpful. Despite the presence of extensive fibrosis, some patients responded to removal from exposure and steroid therapy.