Roles of extracellular matrix in lung diseases

Abstract

Extracellular matrix (ECM) is a non-cellular constituent found in all tissues and organs. Although ECM was previously recognized as a mere "molecular glue" that supports the tissue structure of organs such as the lungs, it has recently been reported that ECM has important biological activities for tissue morphogenesis, inflammation, wound healing, and tumor progression. Proteoglycans are the main constituent of ECM, with growing evidence that proteoglycans and their associated glycosaminoglycans play important roles in the pathogenesis of several diseases. However, their roles in the lungs are incompletely understood. Leukocyte migration into the lung is one of the main aspects involved in the pathogenesis of several lung diseases. Glycosaminoglycans bind to chemokines and their interaction fine-tunes leukocyte migration into the affected organs. This review focuses on the role chemokine and glycosaminoglycan interactions in neutrophil migration into the lung. Furthermore, this review presents the role of proteoglycans such as syndecan, versican, and hyaluronan in inflammatory and fibrotic lung diseases.

Keywords: extracellular matrix; lung fibrosis; lung inflammation; syndecan.

Fig. 1.

Schematic representations of glycosaminoglycan and proteoglycan. The composition of disaccharide unit repeats is schematically illustrated for heparan sulfate, dermatan sulfate (DS), keratan sulfate (KS), chondroitin sulfate (CS) and hyaluronan (HA). Hyaluronan is the only glycosaminoglycan in a free and unsulfated form. All the other glycosaminoglycans are attached to a protein, forming proteoglycans.

Fig. 2.

Glycosaminoglycan-binding domain on CXCL8 dimer. CXCL8 has three binding domains: a high-affinity binding domain, which mediates binding to specific receptors on polymorphonuclear neutrophils; the glycosaminoglycan-binding domain (K20, R60, K64, K67, R68); and the dimer interface (R6), where CXCL8 molecules bind to each other to form dimers. Blue and red show positively and negatively charged regions, respectively.

Fig. 3.

Neutrophil migration in response to rCXCL8 and CXCL8 mutants. a) The CXCL8 mutants (R68A-CXCL8 and K64A/K67A/R68A-CXCL8: TM-CXCL8) recruited more neutrophils into the lungs than recombinant CXCL8 (rCXCL8). b) The CXCL8 mutants appeared more rapidly in plasma after intratracheal instillation than rCXCL8. ^*: p < 0.05 vs rCXCL8. #: p < 0.05 vs control.

Fig. 4.

Role of syndecan-4 in lipopolysaccharide-induced lung inflammation. a) Changes in mRNA for the heparan sulfate proteoglycans after intratracheal instillation of lipopolysaccharide (LPS) into wild-type mice. Among heparan sulfate proteoglycans, syndecan-4 mRNA was rapidly and selectively up-regulated. *: p < 0.05 vs syndecan-4-PBS. b, c) Intratracheal instillation of LPS induced more neutrophil recruitment into the lungs in syndecan-4 deficient mice (Sdc4 KO) than wild-type mice (WT). *: p < 0.05 vs WT.

Fig. 5.

Survival of wild-type and syndecan-4 deficient mice after intranasal instillation of S. pneumoniae. The survival rate of syndecan-4 deficient (Sdc4 KO) mice was significantly worse after intranasal instillation of S. pneumoniae (5.0×10⁶ CFU) than wild-type mice (WT).