Airway Epithelium Stimulates Smooth Muscle Proliferation

Abstract

Communication between the airway epithelium and stroma is evident during embryogenesis, and both epithelial shedding and increased smooth muscle proliferation are features of airway remodeling. Hence, we hypothesized that after injury the airway epithelium could modulate airway smooth muscle proliferation. Fully differentiated primary normal human bronchial epithelial (NHBE) cells at an air-liquid interface were co-cultured with serum-deprived normal primary human airway smooth muscle cells (HASM) using commercially available Transwells. In some co-cultures, the NHBE were repeatedly (x4) scrape-injured. An in vivo model of tracheal injury consisted of gently denuding the tracheal epithelium (x3) of a rabbit over 5 days and then examining the trachea by histology 3 days after the last injury. Our results show that HASM cell number increases 2.5-fold in the presence of NHBE, and 4.3-fold in the presence of injured NHBE compared with HASM alone after 8 days of in vitro co-culture. In addition, IL-6, IL-8, monocyte chemotactic protein (MCP)-1 and, more markedly, matrix metalloproteinase (MMP)-9 concentration increased in co-culture correlating with enhanced HASM growth. Inhibiting MMP-9 release significantly attenuated the NHBE-dependent HASM proliferation in co-culture. In vivo, the injured rabbit trachea demonstrated proliferation in the smooth muscle (trachealis) region and significant MMP-9 staining, which was absent in the uninjured control. The airway epithelium modulates smooth muscle cell proliferation via a mechanism that involves secretion of soluble mediators including potential smooth muscle mitogens such as IL-6, IL-8, and MCP-1, but also through a novel MMP-9-dependent mechanism.

Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc

“…Beklen et al (7) showed that there was an upregulation of both MMP9 and IL-8 in periodontitis. Many studies related with airway epithelium have shown a direct link between the IL-8 secretion and MMP9 expression (15,31,55). Yoon et al (55) have shown that MMP9 protects from ozone induced airway injury may be via posttranscriptional effects on IL-8.…”

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…To date, relatively little attention has been paid to modeling at the cellular or subcellular level in the lung, or to in response to epithelial challenges including physical damage (Malavia et al, 2009;Thompson et al, 2006), viral infection (Tomei et al, 2008) or mechanical strain to simulate the effect of bronchoconstriction on the epithelium (Choe et al, 2003). Similarly, by co-culturing airway epithelial and endothelial cells, it has been shown that cell-cell communication involving soluble endothelial-derived factor(s) causes a significant reduction in paracellular permeability compared to that seen when epithelial or endothelial monolayers are studied in monoculture (Chowdhury et al, 2010).…”

Pathophysiology of bronchial smooth muscle remodelling in asthma

“…Silencing of MMP-9 abrogates the epithelium-dependent increase in BSM cell proliferation. Finally, epithelial injury increases the release of MMP-9 and the expression of Ki67 levels in human BSM cells [157], suggesting that epithelium and BSM strongly interact in asthma.…”

“…In addition, corticosteroids do not prevent TGF-b-induced EMT but decrease it [156]. Furthermore, bronchial epithelium modulates BSM cell proliferation through an IL-6 and MMP-9-dependent mechanism [157]. Silencing of MMP-9 abrogates the epithelium-dependent increase in BSM cell proliferation.…”