Rodent Models of Lung Disease: A Road Map for Translational Research

Abstract

Animal models provide a controlled and reproducible environment for investigating the pathogenesis of human lung diseases. In many cases, the morphological changes associated with a particular model may resemble those seen in their human counterparts, but the corresponding biochemical events may differ, and their timeframe may be significantly reduced. Nevertheless, gaining insight into human disease mechanisms may be possible by employing experimental approaches that minimize the problems associated with extrapolating data from animal studies. Such strategies include using more than one model of a particular disease, employing different routes of administration of the injurious agent, using a variety of animal strains or species, or focusing on biochemical mechanisms common to both the animal model and its human counterpart. For example, rodent models that replicate elastic fiber injury in human pulmonary emphysema have been used to test aerosolized hyaluronan's ability to slow the disease's progression. The same models facilitated the identification of a new biomarker for pulmonary emphysema that may be a real-time indicator of therapeutic efficacy in clinical trials. Therefore, the appropriate use of these models can provide a necessary road map for designing appropriate dosages, delivery routes, timeframes, and endpoints in clinical trials of novel agents for the treatment of lung disease.

Keywords: ALI; animal models; hyaluronan; pulmonary emphysema; pulmonary fibrosis.

Figure 1

Photomicrograph of LPS-treated hamster lung at 24 h, showing a marked influx of neutrophils into alveolar spaces and focal interstitial thickening (arrows) following a single intratracheal instillation of this agent. The population of these cells peaks between 24 and 48 h, then rapidly declines. However, the presence of these cells can be maintained with multiple instillations of LPS, thereby mimicking human ALI more closely—Hematoxylin and Eosin; Original magnification: 200×.

Figure 2

Illustration showing the potential mechanism responsible for the synergy between cigarette smoke and LPS. Following smoke exposure, neutrophils sequestered in alveolar capillaries are activated by LPS, inducing the secretion of elastases that increase their migration into the lung. A deficiency of elastase was previously shown to significantly decrease smoke-induced movement of neutrophils into the extravascular space, supporting the concept that elastase separates these cells from capillary endothelium.

Figure 3

Endothelin may facilitate the influx of neutrophils into the lung. This concept is supported by studies showing that lung injury induced by intratracheal instillation of LPS is mitigated by pretreatment with an ERA (HJP272).

Figure 4

Illustration showing the patchy distribution of elastic fiber injury and airspace enlargement associated with a single intratracheal elastase instillation. The insert depicts a magnified area of lung tissue with fragmented elastic fibers (black lines) and alveolar wall rupture.

Figure 5

Graph showing the correlation between elastase-induced loss of lung surface area and the ratio of free to bound BALF DID following intratracheal instillation of either 5 or 10 units of porcine pancreatic elastase (r = −0.56; p < 0.01). It is hypothesized that the combination of elastase activity and mechanical strain causes the release of intact DID crosslinks from elastin peptides. This process increases the free-to-peptide-bound BALF DID ratio in hamsters intratracheally instilled with elastase [54].

Figure 6

Illustration showing mild alveolar wall injury and rupture following intratracheal instillation of low-dose elastase (left). The instillation of LPS one week later results in an influx of neutrophils, which produce elastases and oxidants that increase elastic fiber damage, alveolar wall rupture, and airspace enlargement (right).

Figure 7

Elastin peptides released from damaged elastic fibers (left) bind to elastin receptor complexes on macrophages (right), inducing the release of proinflammatory cytokines. This mechanism results in a self-perpetuating inflammatory reaction.

Figure 8

Photomicrographs of mouse lungs after 3 months of cigarette smoke exposure. Animals treated with aerosolized HA (left) had significantly less airspace enlargement than smoke-exposed animals given aerosolized saline (right). Hematoxylin and Eosin; original magnification: 100×.

Figure 9

Photomicrographs of mouse lung at 24 h following intratracheal instillation of fluorescein-labeled HA. There was prominent fluorescence associated with elastic fibers (upper), which was confirmed by a photomicrograph of the same area stained for elastic fibers (lower). Reprinted with permission [73]. Original magnification: 400×.

Figure 10

Illustration showing the evolution of BLM-induced pulmonary fibrosis. The fibrotic reaction is maximal around 1 month then gradually recedes. Morphological changes include interstitial fibrosis, cystic airspace dilation, and bronchial epithelialization of distal airspaces (insert).