Alpha-1 Antitrypsin Investigations Using Animal Models of Emphysema

Abstract

Animal models of disease help accelerate the translation of basic science discoveries to the bedside, because they permit experimental interrogation of mechanisms at relatively high throughput, while accounting for the complexity of an intact organism. From the groundbreaking observation of emphysema-like alveolar destruction after direct instillation of elastase in the lungs to the more clinically relevant model of airspace enlargement induced by chronic exposure to cigarette smoke, animal models have advanced our understanding of alpha-1 antitrypsin (AAT) function. Experimental in vivo models that, at least in part, replicate clinical human phenotypes facilitate the translation of mechanistic findings into individuals with chronic obstructive pulmonary disease and with AAT deficiency. In addition, unexpected findings of alveolar enlargement in various transgenic mice have led to novel hypotheses of emphysema development. Previous challenges in manipulating the AAT genes in mice can now be overcome with new transgenic approaches that will likely advance our understanding of functions of this essential, lung-protective serine protease inhibitor (serpin).

Role for Cela1 in Postnatal Lung Remodeling and Alpha-1 Antitrypsin–Deficient Emphysema

“…We have characterized a novel mouse model of AAT-RLD that overcomes many of the limitations of previous models. Whereas humans have one AAT gene (Sepina1), different mouse strains have up to five (Serpina1a-Serpina1e) (10). Furthermore, homozygous deletion of Serpina1a was reported to be embryonic lethal (32).…”

“…The "pallid" mouse has a mutation in the pallidin gene that reduces AAT secretion and develops emphysema at 12 months of age (33,34). However, the "pallid" mouse exhibits multiple other phenotypic and functional anomalies (10,34,35). Mice with knock-in of the human Z-type AAT gene (PiZ mice) have normal concentrations of AAT and no lung phenotype (36).…”

“…One major hurdle to understanding AAT-RLD is the genetic heterogeneity and variable penetrance (3). The lack of a genuine animal model of AAT-RLD has hampered progress in defining the pathogenesis and natural course of this disease (10).…”

Optimising experimental research in respiratory diseases: an ERS statement

“…What are the major unmet needs for modelling and studying COPD? Exposure of animals to cigarette smoke is one of the most relevant models for the study of smoking-associated inflammation and lung pathologies [15,[119][120][121][122][123][124][125][126][127][128][129]. Less well understood is how these inflammatory processes contribute to accelerated decline in lung function, how they persist following smoking cessation, and why they cause predominant airway versus parenchymal disease in subgroups of individuals.…”

“…Experimental studies have access to a broad range of reagents, tissues and intervention strategies that are not available or feasible in clinical research. This has helped to investigate mechanisms of inflammatory processes and emphysema formation [15,[119][120][121][122][123][124][125][126][127][128][129], and implicated protease/anti-protease balance, oxidants/anti-oxidants, apoptosis/proliferation, matrix destruction/ deposition, pro-/anti-inflammatory mediators, lung development (early origin), accelerated ageing, and autoimmune mechanisms in the pathogenesis of COPD (table 10). Similarly, animal models of viral or bacterial infection, and concurrent cigarette smoke exposure have contributed to our understanding of mechanisms of COPD exacerbations [119,123,[133][134][135].…”