| Angiogenesis, apoptosis and re-epithelialization at the foci of recent injury in usual interstitial pneumonia and bronchiolitis obliterans organizing pneumonia | ||
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Re-epithelialization of the newly formed connective tissue is supposed to be a crucial event in the pathogenesis of pulmonary fibrosis (Adamson et al. 1988, Adamson et al. 1990, Selman et al. 2001). Epithelial injury targets type I pneumocytes, but the recovery phase is characterized by proliferation of type II pneumocytes (Adamson et al. 1974, Kawanami et al. 1982, Myers & Katzenstein 1988a and b, Adamson et al. 1990). The epithelial-fibroblast control may be mediated by direct contacts of epithelial cells with fibroblasts of surrounding ECM (Adamson 1990), or by prostaglandin E2 secreted by type II pneumocytes (Taylor et al. 1979, Goldstein & Polgar 1982, McAnulty et al. 1997). Type II pneumocytes are capable of differentiating into type I pneumocytes (Adamson et al. 1974), but cuboidal cells of probably bronchiolar origin can also serve as progenitor cells in alveolar injury (Kawanami et al. 1982). The metaplastic squamous- and bronchiolar-type cells often detected in UIP are probably also of bronchiolar origin (Kawanami et al. 1982, Chilosi et al. 2001).
Laminins are a group of large heterotrimeric glycoproteins, forming large polymerizing networks and providing binding sites for different matrix molecules. The laminin molecule is composed of three chains; the α, β , and γ chain, which are linked together by disulfide bonds to form either a cruciform or T or Y shaped structure. Currently at least 11 different laminin chains and twelve different laminin heterotrimers are known to exist in mammals. Biological functions of laminins are mediated by specific or non-specific receptors present on cell membranes, such as integrins, membrane-bound proteoglycans (e.g. dystroglycan) and other membrane-bound glycoproteins. With collagen IV, laminins form a stable structural framework to which other BM proteins are bound. However, the binding interactions among individual laminins, nidogens, collagens, and other components not only serve as anchors that target BM deposition, but also lead to changes in matrix organization, receptors and cortical cytoskeletal components. Thus, laminins exhibit several essential functional properties in cell adhesion, migration, differentiation, tissue development and mitogenic modulation (reviewed by Colognato & Yurchenco 2000). Cell adhesion is essential for the cellular differentiation and also for the prevention of apoptosis, and laminins and type IV collagen are known to mediate survival signals for epithelial cells (Mooney et al. 1999, Esco et al. 2001).
α3, β 3, and γ 2 chains form laminin-5 (previously called kalinin, epiligrin, nicein or ladsin) heterotrimer. α3 is additionally present in laminins-6 and -7, but there is no knowledge so far that β 3 or γ 2 chains form laminin heterotrimers other than laminin-5. A unique property of the α3 and γ 2 chains is that they are processed in ECM space after secretion, which has not been detected for any other laminin chains. The laminin α3 chain, initially 190 kDa in size, is cleaved into a 160 kDa sized molecule and can be further cleaved into a 145 kDa sized laminin chain by tissue-type plasminogen activator and plasminogen (Goldfinger et al. 1998). The γ 2 chain is synthesized and secreted as a high molecular weight precursor of 155 kDa, which is processed extracellularly to 105 kDa weight (Marinkovich et al. 1992). Recently, matrix metalloproteinase-2 (MMP-2) and membrane type-1 matrix metalloproteinase (MT1-MMP) have been shown to cleave laminin γ 2 chain specifically to generate its truncated form (Giannelli et al. 1997, Koshikawa et al. 2000).
Biological functions of laminin-5 are mediated via integrins α3β 1 (Carter et al. 1991), α6β 1 (Delwel et al. 1993), and α6β 4 (Niessen et al. 1994). Laminin-5 was first found from skin, where it was shown to be located in the anchoring filaments mediating the attachment of keratinocytes to the BM (Rousselle et al. 1991). In skin, the adhesion between epithelial and mesenchymal cells is mediated through the chain of proteins consisting of hemidesmosomal proteins, α6β 4 integrin, laminin-5 and type VII collagen (Rousselle 1991 and 1997, reviewed by Jones et al. 1998). Laminin-5 also interacts with laminins-6 or -7 by forming disulfide-bonded complex, and this association may provide a mechanism for linking laminin-5 with BM proper (Champliaud et al. 1996). Mutations in all three laminin chain-coding genes cause detachment of cells from BM and blister formation (Pulkkinen et al. 1994a,b, Kivirikko et al. 1995). Laminin-5 is also highly expressed especially by migrating keratinocytes in wounded skin in establishing a new BM-zone (Pyke et al. 1994). Thus, laminin-5 has important roles in the attachment of epithelial cells.
In addition to the role of laminin-5 in re-epithelialization and BM integrity, it induces cell migration (Giannelli et al. 1997, Goldfinger et al. 1998, Salo et al. 1999). This functional conversion may be modulated by the extracellular processing of laminin chains (Giannelli et al. 1997, Goldfinger et al. 1998, Koshikawa et al. 2000). Laminin-5 is also known to modulate T cell proliferation, activation and apoptosis (Vivinus-Nebot et al. 1999, Sato et al. 1999), and it may prevent hypoxia-mediated apoptosis of human corneal epithelial cells (Esco et al. 2001).
Laminin-5 has been observed in BMs of both squamous and glandular epithelia in several locations, e.g. skin, lung, breast, intestine and prostate (Rousselle et al. 1991, Kallunki et al. 1992, Pyke et al. 1994, Virtanen et al. 1995, Hao et al. 1996). Recently, expression of laminin-5 has also been found in vascular smooth muscle cells (Kingsley et al. 2002). By in situ hybridization the γ 2 chain was found to be highly expressed in epithelial cells of fetal bronchi and alveoli (Kallunki et al. 1992). In normal adult lung, laminin-5 γ 2 chain is localized in the BMs of bronchiolar and alveolar epithelium (Mizushima et al. 1998).
No previous studies comparing the extent of re-epithelialization in BOOP and in UIP were available. Neither were there studies on the role of laminin-5 in re-epithelialization of the newly formed connective tissue in pulmonary fibrosis.