Table 1

Naturally occurring mice strains that develop airspace enlargement and emphysema

MouseGenetic/physiological defectPhenotypeLung phenotypeReference
CTL=cytotoxic T lymphocytes; NK=natural killer cells.
Tight skin (Tsk+/–)• Duplication of fibrillin 1 (Fbn-1), main component of 10–12 nm extracellular microfibrils (causes Marfan’s syndrome in man)• Tight skins, hyperplasia of subcutaneous connective tissues, ↑ growth of cartilage and bone, small tendons, hyperplasia of tendon sheaths• Panlobular emphysema develops after 4 days of life 58– 63
• Possible dominant negative effect of Tsk Fbn-1 by incorporation into microfibrils, rendering them susceptible to proteolysis• Emphysema is preceded by a low level macrophage-neutrophil alveolitis
Beige (Bg)• 5 kb deletion in Lyst (causes Chediak-Higashi syndrome in man)• Dilution of coat colour, recurrent infections, giant granules• Normal at birth, abnormal neonatal alveolarisation 60, 63– 65
• Lysosomal missorting of proteins such as elastase, glucuronidase and cathepsin G• Adult lungs: fewer alveoli, smooth terminal air ducts lacking the normal complement of alveolar struts
• Intracellular vesicle transport defect and generalised immunodeficiency in mice and humans (abnormal function of NK cells, CTL)
Blotchy• X-linked defective copper transport• Aortic aneurysms, reduced skin tensile, develop osteoarthrosis• Enlarged airspaces 66– 68
• Abnormal RNA splicing of the mouse homologue of copper ion transporting ATPase, Atp7A (Menke gene; Menkes disease in humans)• Disruption of elastic fibres
• Impaired lysyl oxidase, abnormal collagen and elastin cross linking
Pallid (Pa)• 1 of 13 platelet storage pool deficiency mouse mutants• Prolonged bleeding time, pigment dilution, kidney lysosomal enzyme elevation• Progressive emphysema from 1 month 60, 69– 71
• Nonsense mutation at codon 69 in Pallidin which interacts with syntaxin 13: important in vesicle docking and fusion• Serum α1-antitrypsin deficiency, abnormal otolith formation• ↑ elastase, ↓ lung elastin
• Defect in organelle biosynthesis• ↑ intracytoplasmic crystalloid inclusions related to collagen degradation in pulmonary macrophages
Osteopetrotic (Op/Op)• Deficient in macrophage colony stimulating factor• Osteopetrosis• Young mice have reduced numbers of lung macrophages (which return to normal as they age) and emphysema 72
• Macrophages release more MMPs
• BAL IL-3 is increased