-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. chronic obstructive pulmonary disease CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is an increasingly important cause of morbidity and mortality. COPD is now the fifth leading cause of death worldwide (109), and recent estimates suggest that the prevalence is as high as 9 -10% of adults over age 40 (38, 131). In the developed world, cigarette smoking is by far the most important risk factor for COPD. Exposure to air pollution particles, occupational exposures to dusts and fumes (39), and, in the developing world, exposure to biomass fuels used for cooking is also believed to be etiological agents of COPD (38).There are few animal models of COPD related to air pollution particles, dusts and fumes, and biomass fuels; most COPD models have either used cigarette smoke or other approaches, including genetic modifications to mice, believed to reproduce some of the mechanisms behind cigarette smoke. We have recently reviewed mechanistic studies of smoke-exposed animal models (16). In this paper, we will focus on the pros and cons of different COPD animal models.The first question to ask in this context is what would constitute a perfect model of human COPD. This is not a simple question because human COPD consists of at least four anatomic lesions (further defined below): emphysema, small airway remodeling (including goblet cell metaplasia), chronic bronchitis, and pulmonary hypertension; a given patient may have any or all of these lesions. In addition, COPD patients may develop acute exacerbations that are believed to have an infectious basis. To further complicate matters, no matter which lesions are present, COPD develops and is slowly progressive over many years.Because COPD is closely related to the underlying anatomy of the lung, a good animal model should have pulmonary anatomy similar to that of humans. The fundamental mechanisms behind COPD should be similar in animal models and humans. The ideal model would allow the investigator to produce the various different anatomic lesions just listed, all in a short period of time. Unfortunately, all of the known animal models meet only some of the above criteria, and even another human would probably not meet all of them, because, as noted above, there is considerable human to human variation in th...

The cells and proteases that mediate cigarette smoke-induced emphysema are controversial, with evidence favoring either neutrophils and neutrophil-derived serine proteases or macrophages and macrophage-derived metalloproteases as the important effectors. We recently reported that both macrophage metalloelastase (MMP-12) and neutrophils are required for acute cigarette smoke-induced connective tissue breakdown, the precursor of emphysema. Here we show how these disparate observations can be linked. Both wild-type (MMP-12 +/+) mice and mice lacking MMP-12 (MMP-12 -/-) demonstrated rapid increases in whole-lung nuclear factor-kappaB activation and gene expression of proinflammatory cytokines after cigarette smoke exposure, indicating that a lack of MMP-12 does not produce a global failure to upregulate inflammatory mediators. However, only MMP-12 +/+ mice demonstrated increased whole-lung tumor necrosis factor-alpha (TNF-alpha) protein or release of TNF-alpha from cultured alveolar macrophages exposed to smoke in vitro. Levels of whole-lung E-selectin, an endothelial activation marker, were increased in only MMP-12 +/+ mice. These findings suggest that, acutely, MMP-12 mediates smoke-induced inflammation by releasing TNF-alpha from macrophages, with subsequent endothelial activation, neutrophil influx, and proteolytic matrix breakdown caused by neutrophil-derived proteases. TNF-alpha release may be a general mechanism whereby metalloproteases drive cigarette smoke-induced inflammation.

Mice lacking tumor necrosis factor-alpha (TNF-alpha) receptors (TNFRKO mice) do not develop an inflammatory infiltrate or matrix breakdown after a single acute cigarette smoke exposure. To determine the role of TNF-alpha in the long-term development of emphysema, mice were exposed to smoke for 6 months. TNFRKO mice demonstrated an 11% increase in mean linear intercept; wild-type mice had a 38% increase. TNFRKO mice had 65% fewer neutrophils and no increase in macrophages in lavage fluid. Whole lung matrix metalloprotease (MMP)-2, MMP-9, MMP-12, MMP-13, and matrix type-1 (MT1)-MMP proteins were increased in wild-type mice, but smaller increases in MMP-12, MMP-13, and MT1-MMP were also seen in TNFRKO mice. Lavage matrix breakdown products were elevated in wild-type mice and only partially reduced by anti-neutrophil antibody, implying both neutrophil- and non-neutrophil-mediated matrix breakdown. We conclude that TNF-alpha-mediated processes, probably driving neutrophil influx, are responsible for approximately 70% of airspace enlargement and the majority of inflammatory cell influx/matrix breakdown in the mouse model. TNF-alpha causes increased MMP production, but some increased MMP activity is present even in TNFRKO mice. These findings imply a second TNF-alpha-independent process, possibly related to direct MMP attack on matrix, that produces the remaining 30% of airspace enlargement.

Human pancreatic islet transplantation offers diabetic patients tight glucose control but has low graft survival rates. The immunosuppressive drugs that are administered to graft recipients lack the antiinflammatory benefits of corticosteroids because of their diabetogenic effects. The serum protease inhibitor ␣1-antitrypsin (AAT) possesses antiinflammatory properties and reduces cytokine-mediated islet damage. In the present study, diabetic mice were grafted with allogeneic islets and treated with AAT monotherapy (n ‫؍‬ 24). After 14 days of treatment, mice remained normoglycemic and islet allografts were functional for up to 120 treatment-free days. After graft removal and retransplantation, mice accepted same-strain islets but rejected third-strain islets, thus confirming that specific immune tolerance had been induced.