Table 2

Examples of mouse models where “knockout” of a protein leads to the development of airspace enlargement due to a failure of alveogenesis or emphysema

GenePhenotypeReference
–/– = null mice.
For a detailed review of developmental phenotypes see references 26 and 27.
Gene deletions that interfere with alveogenesis
Platelet derived growth factor A (PDGF-A) –/–• Prenatal block in the spreading of PDGF receptor-α+ cells resulting in a lack of myofibroblasts, an absence of tropoelastin expression, and failed alveolar septation 30, 31
• Postnatally mice are half the size of wild type litter mates and do not survive beyond 6 weeks
Fibroblast growth factor receptor (FGFR) 3 and 4 –/–• Mice lacking both FGFR 3 and 4 (but not FGFR 4 alone) are normal at birth but do not form secondary septae or alveoli 32
• Increased elastin deposition subsequent to alveogenesis, growth retardation
Fibulin-5/DANCE –/–• Integrin ligand for αvβ3, αvβ5 and α9β1, probably acts as an organising anchor between cells and elastic fibres 29
• Abnormal distal airway development and alveogenesis due to defective development of elastic fibres.
• Tortuous aorta and cutis laxa
Elastin –/–• Fewer and dilated distal air sacs at birth and arrested terminal airway development (the mice die from obstructive arterial disease due to subendothelial cell proliferation and a reorganisation of smooth muscle) 28
Retinoic acid receptor (RAR) γ –/–• Increased alveolar size is worsened by co-deletion of retinoid X receptor-α 34
• Decreased tropoelastin mRNA and whole lung elastic tissue
Forkhead Box F1 (Foxf1) transcription factor +/–• Severity of the pulmonary abnormalities correlates with the levels of Foxf1 mRNA, those with lowest levels have defects in alveolarisation and vasculogenesis 35
• Lung haemorhage due to disruption of the mesenchymal-epithelial cell interfaces in the alveolar and bronchiolar regions
Tumour necrosis factor- α converting enzyme (TACE/ADAM–17) –/–• Transmembrane metalloprotease-disintegrin cleaves cell surface proteins including cytokines and growth factors 37
• Impaired branching morphogenesis, defects in epithelial cell proliferation and differentiation, and delayed vasculogenesis
• Lungs fail to form normal saccular structures, fewer peripheral epithelial sacs, deficient septation and thick walled mesenchyme
POD–1 (Tcf21, capsulin, epicardin) –/–• Basic-helix-loop-helix transcription factor expressed at sites of mesenchymal-epithelial interaction in the lung, kidney, intestine and pancreas 36
• Hypoplastic lungs, abnormal lung branching, lacking alveoli and type II pneumocytes. Mice die in perinatal period
Gene deletions that cause airspace enlargement after birth
Tissue inhibitor of metalloproteinases (TIMP)-3 –/–• Progressive air space enlargement evident at 2 weeks 39
• Aged animals have reduced collagen, enhanced degradation of collagen in the peribronchiolar space, and disorganisation of collagen fibrils in the alveolar interstitium
• Mice are moribund at 13 months
• Increased MMP activity without an increase in inflammatory cell infiltration
Surfactant protein D –/–• Progressive pulmonary emphysema from 3 weeks of age 38
• Lipid-laden alveolar macrophages, increased oxidant production and reactive oxidant activate NF-kappa B and MMP expression in alveolar macrophages
• SP-D plays an inhibitory role in the regulation of NF-kappa B in alveolar macrophages
Gene deletions protecting against emphysema after challenge
Macrophage elastase (MMP-12) –/–• Normal lung development 5
• Protection from cigarette induced emphysema
Interleukin 1β type 1 receptor and type 1 and 2 TNF-α receptors• Protected from porcine pancreatic elastase-induced emphysema 42
• Individual gene deleted mice are not protected