Pulmonary fibrosis: cytokines in the balance

Abstract

Pulmonary fibrosis can complicate diverse pulmonary and systemic pathologies. In many cases the underlying cause remains unidentified. Mortality from the disease is increasing steadily in the UK and USA. The clinical features are well-described, but patients frequently present at an advanced stage, and current treatments have not improved the poor prognosis. There is a compelling need to identify the fibrotic process earlier and to develop new therapeutic agents. Increased collagen deposition is central to the pathology and interest over the last decade has focused on the role of cytokines in this process. These polypeptide mediators are believed to be released from both circulating inflammatory and resident lung cells in response to endothelial and epithelial injury. Key cytokines currently implicated in the fibrotic process are transforming growth factor-beta, tumour necrosis factor-alpha and endothelin-1. This article outlines the evidence implicating these mediators in the pathogenesis of pulmonary fibrosis and also considers the possible role of cytokines with antifibrotic effects, such as interferon-gamma. The "balance" of positively and negatively regulating cytokines is discussed, and the potential for interaction with other factors including viruses, hormones and altered antioxidant status is also considered. Finally, potential novel therapeutic approaches are discussed, together with suggestions for future studies and clinical trials. As the outcomes of different avenues of research over the last ten years are brought together, it is clear that there is now a hitherto unrivalled opportunity to begin to tackle the treatment of this devastating disease.

Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans

“…The common paradigm postulates an initial alveolar injury, which triggers an inflammatory response and, subsequently, fibrosis (4). The mainstay of the current therapeutic approach to UIP is suppression of inflammation.…”

Impact of Interleukin-13 Responsiveness on the Synthetic and Proliferative Properties of Th1- and Th2-Type Pulmonary Granuloma Fibroblasts

“…[1][2][3] Transforming growth factor (TGF)-␤ is regarded as the premier pathological cytokine in chronic pulmonary fibrosis because of its enhanced presence in clinical idiopathic pulmonary fibrosis (IPF) 4,5 and its potent role in experimental fibrosis under a number of conditions. 6 -8 Interestingly, data published recently suggested that the synthesis of TGF-␤ during experimental pulmonary fibrosis was regulated by interleukin (IL) -13, 8 a Th2-type cytokine whose actions were believed to be limited to that of immune cell regulation.…”

Idiopathic Interstitial Pneumonias: Pathomechanisms and Therapeutic Options

“…Zahlreiche experimentelle und klinische Daten legen eine über− ragende pathogenetische Rolle von TGF−â bei fibrosierenden Lungenerkrankungen nahe [46,47]. Auf in vitro Ebene konnte u. a. gezeigt werden, dass TGF−â Fibroblastenchemotaxis, Fibro− blastenproliferation und Fibroblastendifferenzierung zu Myofi− broblasten fördert und die Kollagensynthese durch Fibroblasten erheblich steigert [46].…”

“…Die Applikation eines TGF−â−Antikörpers oder eines löslichen TGF−â−Rezeptors führt zu einer signifikanten Reduktion der pulmonale Kollagendeposi− tion in diesem Modell [49,50] [51]. Neben TGF−â scheinen auch zahlreiche weitere Wachstumsfak− toren wie PDGF (platelet−derived growth factor), CTGF (connec− tive tissue growth factor) oder IGF−I (insulin−like growth factor I) in die pathogenetische Sequenz fibrosierender Lungenerkran− kungen integriert zu sein [47].…”