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Genetic predisposition and pathogenetic mechanisms of interstitial lung diseases of unknown origin

¹ Dept Respiratory Disease, University Hospital Gasthuisberg, Leuven, Belgium. ² Dept Respiratory Disease, Royal Brompton Hospital, London, UK. ³ Dept Respiratory Disease, University Hospital, Heraklion, Greece. ⁴ Dept Respiratory Disease, University Hospital of Maastricht, Maastricht, the Netherlands. ⁵ Dept Respiratory Disease, Southmead Hospital, Bristol, UK. ⁶ Zentrüm for Medizin und Biowissenschaften, Forschungszentrum Borstel, Borstel, Germany. ⁷ Dept Clinical and Experimental Medicine, University School of Medicine, Padua, Italy. ⁸ Division of Therapeutics, Queen's Medical Centre, Nottingham, UK. ⁹ Dept Respiratory Disease, University Hospital, Parma, Italy. ¹⁰ Länsi-Uusimaa Hospital, Tammisaari, Finland. ¹¹ Dept Respiratory Disease, Hospital Clinic, Barcelona, Spain

CORRESPONDENCE: G.M. Verleden, University Hospital Gasthuisberg, Dept Respiratory Diseases, 49, Herestraat, B-3000, Leuven, Belgium. Fax: 32 16346803

Keywords: interstitial lung disease, lymphangioleiomyomatosis, predisposition, pulmonary fibrosis, sarcoidosis, systemic sclerosis

Received: March 8, 2001
Understanding of the cellular and cytokine interactions associated with inflammation and fibrosis in interstitial lung diseases (ILDs) has increased substantially during the past few years. Presently, many agents are known to have the ability to induce ILDs, although only a small percentage of exposed individuals will develop the disease. In addition, the majority of ILDs are of unknown origin and many are labelled "idiopathic". Therefore, host susceptibility, genetic factors and, possibly, environmental cofactors may be important for the clinical expression of ILDs.

The present review reports evidence of the genetic predisposition to develop ILDs of unknown origin, more specifically sarcoidosis, idiopathic pulmonary fibrosis (IPF), lymphangioleio-myomatosis and ILDs, in systemic sclerosis. For instance, for sarcoidosis and IPF several histocompatibility antigens have been associated with the development and/or the clinical presentation of the disease. Furthermore, there are also several types of ILD that are associated with inherited disorders, of which the tuberous sclerosis complex is only one example. This clearly indicates that pulmonary fibrosis can be influenced by genetic factors. Familial occurrence of sarcoidosis and IPF is also well known, although the exact modes of inheritance are debatable.

Several studies have shown that extrinsic factors, such as single or multiple fibrosing agents, probably contribute to the development of clinical ILDs of unknown origin. It is probable that some of these studies deal with patients who do not have classical IPF, as recently defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus. Therefore, the true role of these extrinsic factors in the development of IPF, or even sarcoidosis, remains speculative.

With the help of animal studies and, more specifically, by using knock-out mice, it may be possible in the near future to unravel at least some of the genes that are responsible for the increased susceptibility of the development of interstitial lung diseases.