Airway smooth muscle remodels pericellular collagen fibrils: implications for proliferation.
Airway wall remodeling comprises a broad range of structural changes including increases in the volume of airway smooth muscle (ASM) and fibrillar collagen. The impact of fibrillar collagen remodeling on ASM proliferation was investigated. Human ASM cultured on type I fibrillar collagen remodeled the collagen substrate by both degradation (collagenolysis) and formation of networks comprised of thicker reticular collagen fibrils (fibrillogenesis). In cultures maintained on fibrillar collagen, the levels of matrix metalloproteases (MMPs) -1 and -14 mRNA and active MMP-2 were higher than in cultures maintained on nonfibrillar type I collagen (gelatin) or plastic. Although there was no apparent increase in cytotoxicity or apoptosis, the number of ASM was lower on fibrillar collagen than on gelatin or plastic for control conditions. Furthermore, maintenance on fibrillar collagen attenuated basic fibroblast growth factor-stimulated increases in cell number and the percentage of cells entering S-phase. In cultures maintained on fibrillar collagen, the MMP inhibitor ilomastat (2.5 microM) 1) attenuated collagenolysis, 2) enhanced fibrillogenesis, and 3) inhibited proliferation. In contrast, knockdown of the beta1-integrin gene in ASM maintained on fibrillar collagen led to an increase in proliferation and reduced MMP-1 and -14 expression. Thus, ASM remodel the pericellular environment by degrading collagen fibrils and spinning them into larger collagen assemblies. Moreover, the collagen fibrils limit proliferation and activate autocrine MMPs in a beta-integrin-dependent manner, suggesting a potential negative feedback on modeling executed through fibrillar collagen activation of beta1-integrins.
Schuliga
Michael
M
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Ong
Siau Chi
SC
Soon
Lilian
L
Zal
Fatemeh
F
Harris
Trudi
T
Stewart
Alastair G
AG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056151:Airway Remodeling / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D024022:Fibrillar Collagens / Q000378:metabolism* / Q000648:ultrastructure; D055785:Gene Knockdown Techniques; D006801:Humans; D006877:Hydroxamic Acids; D007211:Indoles / Q000494:pharmacology; D019012:Integrin beta1 / Q000235:genetics; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D024022:Fibrillar Collagens; D006877:Hydroxamic Acids; D007211:Indoles; D019012:Integrin beta1; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D020782:Matrix Metalloproteinases; C119203:ilomastat