Fibrillin-1 staining anomalies are associated with increased staining for TGF-beta and elastic fibre degradation; new clues to the pathogenesis of emphysema.
We recently demonstrated aberrant staining of fibrillin-1 in lung tissue specimens with emphysematous lesions. In this study, we have extended this observation by an elaborate analysis of the elastic fibre. Using domain-specific antibodies to fibrillin-1, and to other elastin fibre-associated molecules, lung tissue derived from patients without obvious clinical emphysema, but harbouring various degrees of microscopical emphysematous lesions, was analysed. In addition, the fibrillin-regulated growth factor TGF-beta was studied. Electron microscopy and biochemical analysis of desmosine (a marker for elastin) were also performed. Results were compared with lung tissue derived from patients with clinical emphysema. Domain-specific antibodies recognizing the C-terminal, N-terminal, and middle part of fibrillin-1 showed aberrant staining patterns associated with increasing degrees of microscopical emphysema. Staining for elastin, emilin-1, and fibulin-2 was, however, not aberrant. TGF-beta staining was markedly increased. On the electron microscopic, but not light microscopical, level, initial elastic fibre degradation was noticed in specimens with microscopical emphysema. Lung specimens from patients with clinical emphysema also displayed fragmented fibrillin-1 staining and, in addition, displayed extensive degradation of the elastic fibre. The results suggest that fibrillin-1 anomalies and TGF-beta overexpression are associated with initial events occurring during the emphysematous process. Based on these and other data, a mechanism for emphysematogenesis is proposed.
Department of Biochemistry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Mieke M J F
MM
Koenders
Ronnie G
RG
Wismans
Barry
B
Starcher
Ben C J
BC
Hamel
Richard P N
RP
Dekhuijzen
Toin H
TH
van Kuppevelt
D016022:Case-Control Studies; D004547:Elastic Tissue / Q000473:pathology; D004549:Elastin / Q000032:analysis / Q000378:metabolism; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000032:analysis*; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D011656:Pulmonary Emphysema / Q000378:metabolism* / Q000473:pathology; D013194:Staining and Labeling; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000032:analysis*; D054392:Adipokines
D004549:Elastin; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines