tetrathiomolybdate and Pulmonary-Fibrosis

Idiopathic pulmonary fibrosis is the most common form of the interstitial lung diseases and is characterized by chronic progressive pulmonary parenchymal fibrosis. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there remains no effective therapy for this disease. Therapies initially aimed at inflammation have proven ineffective, and newer strategies targeting aspects of aberrant wound repair involving alveolar epithelial cells or septal endothelial cells are now being investigated. Therapeutic strategies include the anti-fibrotic agents pirfenidone and interferon-gamma. Agents targeting specific cytokines, including connective tissue growth factor, transforming growth factor-beta and chemokines, are being evaluated. The restoration of oxidant balance and inhibition of leukotrienes represent other strategies. Additionally, the role of the coagulation/fibrinolytic systems and angiogenesis has also been examined.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antioxidants; Connective Tissue Growth Factor; Humans; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Lung; Molybdenum; Neovascularization, Pathologic; Pulmonary Fibrosis; Pyridones; Randomized Controlled Trials as Topic

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing disease of the distal air spaces of the lung of unknown aetiology. IPF is usually fatal with a median survival of < 3 years. There are currently no effective pharmacotherapeutic agents for the treatment of IPF. In this review, unifying concepts on the pathogenesis of IPF based on understanding of host responses to tissue injury are presented. These host responses involve tightly regulated and contextually orchestrated inflammatory and repair processes. Dysregulation of either of these processes can lead to pathological outcomes. Fibrosis results from an exaggerated or dysregulated repair process that proceeds 'uncontrolled' even after inflammatory responses have subsided. Disease heterogeneity may arise when inflammation and repair are in different (dys)regulatory phases, thus accounting for regional disparity. Usual interstitial pneumonia (UIP), the histopathological correlate of clinical IPF, represents a more fibrotic tissue reaction pattern and for which anti-inflammatory agents are ineffective. Emerging 'antifibrotic' drugs and strategies for UIP/IPF are discussed. The importance of accurately phenotyping a highly heterogeneous disease process that may require individualised and 'combined' therapies is emphasised.

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Connective Tissue Growth Factor; Eicosanoids; Endothelin-1; Humans; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Interferon-gamma; Molybdenum; Protein Kinase Inhibitors; Proteins; Pulmonary Fibrosis; Pyridones; Recombinant Proteins; Relaxin; Renin-Angiotensin System; Tumor Necrosis Factor-alpha

Pulmonary fibrosis (PF) is characterized by an increase in the number of fibroblasts and an accumulation of collagen fibers in the extracellular matrix (ECM). The members of the copper-dependent lysyl oxidase (LOX) enzyme family regulate the collagen accumulation in the ECM. Tetrathiomolybdate (TM) is a copper chelator. The present study reported the effect of TM on the expression of LOX proteins (LOX, LOXL1, and LOXL2), collagen digestion enzymes (MMP2 and MMP8), and TIMP1 (a collagenase inhibitor) in PF. The PF in mice was induced by intratracheal bleomycin instillation. Adult mice were divided into four groups: mice dissected after 21 days of the first bleomycin (0.08 mg/kg, single dose) treatment (I) and their controls (II), and mice treated with TM for 1 week (1.2 mg/day/mice for the first 4 days and 0.9 mg/day/mice for the last 3 days) after 14 days of the first bleomycin instillation and dissected in the 21st day of the experiment (III) and their controls (IV). Mice in groups III and IV were fed a low-copper (2 mg/kg) diet during the last 7 days of the experiment. The fibrosis score in the lung was determined under a microscope. The expressions of collagen-I, LOX, MMP, and TIMP1 proteins were analyzed by Western blotting in the lung. Mice lungs with fibrosis were characterized by an overexpression of collagen-I, LOX, MMP, and TIMP1 proteins in addition to an accumulation of collagen fibers. TM treatments significantly regressed the overexpression of these proteins in the fibrotic mice lung. In conclusion, TM treatments can be used for the regression of PF, by decreasing collagen-I protein expression and accumulation.

Topics: Animals; Bleomycin; Chelating Agents; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 8; Mice; Mice, Inbred C57BL; Molybdenum; Protein-Lysine 6-Oxidase; Pulmonary Fibrosis

Tetrathiomolybdate is an anticopper drug with a unique mechanism of action. Tetrathiomolybdate complexes copper to protein and itself, rendering the copper unavailable for cellular uptake. It was originally developed for Wilson's disease, and is now being developed as an antiangiogenic agent for the treatment of cancer. Many angiogenic cytokines require normal levels of copper, and lowered copper levels reduce cytokine signaling while cellular copper requirements are met. Cytokines of fibrosis and inflammation may be similarly copper dependent, since tetrathiomolybdate inhibits bleomycin induced pulmonary inflammation and fibrosis. The basis for this inhibition was evaluated here by examination of tetrathiomolybdate effects on cytokines in lung pathophysiologically important in the bleomycin mouse model of pulmonary damage. Results in mice injected endotracheally with bleomycin confirmed that tetrathiomolybdate therapy was effective in reducing fibrosis. This effect was associated with significant inhibition of bleomycin-induced tumor necrosis factor alpha and transforming growth factor beta expression in lung homogenates. These effects were shown to be independent of one another. This indicates that tetrathiomolybdate therapy can be effective even when fibrosis is at a more chronic stage, wherein inflammatory cytokines are playing a diminishing role. The inhibition of tumor necrosis factor alpha suggests that diseases of tumor necrosis factor alpha overexpression are also potential targets of tetrathiomolybdate therapy.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Bleomycin; Ceruloplasmin; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Lung; Mice; Mice, Inbred CBA; Molybdenum; Pulmonary Fibrosis; Time Factors

Tetrathiomolybdate (TM), a drug developed for the treatment of Wilson's disease, produces an antiangiogenic effect by reducing systemic copper levels. Several angiogenic cytokines appear to depend on normal levels of copper for activity. In both animal tumor models and in cancer patients, TM therapy has proved effective in inhibiting the growth of tumors. We have hypothesized that the activities of fibrotic and inflammatory cytokines are also subject to modulation by the availability of copper in a manner similar to angiogenic cytokines. As a first step in evaluating whether TM plays a therapeutic role in diseases of inflammation and fibrosis, we studied the effects of TM on a murine model of bleomycin-induced pulmonary fibrosis. Oral TM therapy resulted in dose-dependent reduction in serum ceruloplasmin, a surrogate marker of systemic copper levels. Significant decreases in systemic copper levels were associated with marked reduction in lung fibrosis as determined on the basis of histopathologic findings and a biochemical measure of fibrosis. The protection afforded by TM was also reflected in significantly reduced bleomycin-induced body-weight loss. In the next phase of this work, we will seek to determine the mechanisms by which TM brings about this therapeutic benefit.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Bleomycin; Body Weight; Ceruloplasmin; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hydroxyproline; Lung; Mice; Mice, Inbred CBA; Molybdenum; Pulmonary Fibrosis