Scleroderma

Tamiko R. Katsumoto, Shelia M. Violette, and Dean Sheppard
Received 27 May 2011; Accepted 15 August 2011

Interstitial lung disease (ILD) is a commonly encountered complication of systemic sclerosis (SSc) and accounts for a significant proportion of SSc-associated morbidity and mortality. Its pathogenesis remains poorly understood, and therapies that treat SSc ILD are suboptimal, at best. SSc ILD pathogenesis may share some common mechanisms with other fibrotic lung diseases, in which dysregulation of lung epithelium can contribute to pathologic fibrosis via recruitment or in situ generation and activation of fibroblasts. TGFβ, a master regulator of fibrosis, is tightly regulated in the lung by the integrin αvβ6, which is expressed at low levels on healthy alveolar epithelial cells but is highly induced in the setting of lung injury or fibrosis. Here we discuss the biology of αvβ6 and present this integrin as a potentially attractive target for inhibition in the setting of SSc ILD.

Systemic sclerosis (SSc), also known as scleroderma, is a connective tissue disease of unknown etiology that is characterized by fibroproliferative changes in multiple organs, as well as microvascular and immunologic dysregulation. One of the most morbid conditions associated with SSc is interstitial lung disease (ILD), which occurs in 25–90% of SSc patients, depending on the detection methods used and the demographics of the population being studied. The pathologic mechanisms responsible for the initiation and maintenance of SSc ILD remain poorly characterized. Approximately 42% of patients with SSc ILD will die of disease progression within 10 years of diagnosis, and currently no curative therapies exist to combat this morbid complication.

Much of the research literature on SSc-associated fibrosis has focused on the roles of fibroblasts and myofibroblasts, the effector cells that are ultimately involved in the production of collagen and other extracellular matrix (ECM) proteins. However, the development of fibrosis in SSc is indeed a complex process involving crosstalk amongst multiple cell types, including epithelial, endothelial, immune, and mesenchymal cell types.

In idiopathic pulmonary fibrosis (IPF), a progressive fibrosing lung disease that has a median survival of between two and three years, the principle defect is thought to be recurrent epithelial injury with resultant epithelial cell senescence and/or apoptosis. Epithelial injury can lead to the recruitment and activation of fibroblasts, which can be derived from resident fibroblasts, circulating fibrocytes, or the differentiation of epithelial cells, endothelial cells, or pericytes into fibroblasts.

The best characterized of these changes in cell differentiation involves epithelial cells and has been termed epithelial-to-mesenchymal transition (EMT). Alveolar type II epithelial cell (AT2) injury has long been observed in lung biopsies from patients with ILD, and recent animal data suggests a causal relationship between AT2 injury and fibrosis. Sisson et al. recently demonstrated that targeted deletion of AT2 cells, using diphtheria toxin driven by a specific lung epithelial cell promoter leads directly to lung fibrosis. The most convincing evidence for the contribution of EMT to lung fibrosis came from studies by Kim et al., who used genetic fate-mapping methods to demonstrate the capacity of alveolar epithelial cells to undergo EMT in an established mouse model of lung fibrosis. Based on these data and others, injured alveolar epithelial cells are viewed as potential drivers of pathologic pulmonary fibrosis.

Continue reading the full review paper, by downloading it from the link provided below.