Pulmonary Fibrosis, literally meaning the abnormal formation of fibre like scar tissue in the lungs. The scar formation is preceded by, and associated with inflammation. It is a complicated, chronic, terminal lung disease that can derive from many different causes. If the disease progresses, the lung tissues eventually thicken and become stiff, causing breathlessness. Characterized by the excessive and deranged accumulation of extra cellular matrix (ECM) proteins in the lungs. Even after diagnosis the prognosis is poor, and along with the physical hardships, the psychological difficulties that arise can be crippling. In recent years it has become clear that patients with pulmonary fibrosis have different histological appearances and clinical presentations resulting from the heterogeneous nature of this group of inflammatory and interstitial fibrosing diseases. A new classification has identified four subtypes: acute interstitial pneumonia (AIP), non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), and usual interstitial pneumonia (UIP).
There are over 140 known causes or associations with pulmonary fibrosis. It appears that the lung is reacting to some insult by developing inflammation and subsequent fibrosis. The nature of the initial insult is not always known and although we sometimes, say that pulmonary fibrosis is due to a given disease (for example, "sarcoidosis") we may not often know the specific causes of those diseases either. The most frequent causes of pulmonary fibrosis are sarcoidosis, fibrosis associated with certain occupational diseases, and pulmonary fibrosis in which the causes are not known are called as idiopathic (IPF).
Regardless of the origin interstitial lung fibrosis (ILF), is invariably associated with fibrosing alveolitis characterized by inflammation and an over exuberant repair process preceded by an excess number of fibroblasts an absolute increase in lung collagen content, and abnormality in the ultra structural appearance and spatial distribution of collagen types. Accumulation of collagen-rich ECM in the lung interstitium and peripheral air spaces causes a derangement of the alveolar wall and loss of functional capillary units.
IPF, the most common interstitial lung disease in humans, typically affects individuals aged 40 through 70, with slight male predominance, and shares some of the histological and biochemical features of ILF of known etiological origins. Though few epidemiological data exist on the occurrence of pulmonary fibrosis but recent findings suggest a much higher prevalence (up to 29 per 100,000 persons) than was previously assumed. It appears that worldwide mortality due to pulmonary fibrosis is increasing, particularly in elderly persons.
Pathogenesis
Unknown injuries induce alveolar epithelial damage resulting in alveolar epithelial cell activation, wound clot formation and fibrin deposition. Stimulated alveolar epithelial cells secrete growth factors and induce migration and proliferation of fibroblasts that secrete extra cellular matrix proteins, mainly collagens. Hyperplasic alveolar epithelial cells regenerate the alveolar epithelium by migration over the provisional fibrinous matrix. Activated fibroblasts may induce apoptosis of regenerating alveolar epithelial cells, impairing alveolar epithelial repair. An imbalance of pro- and antifibrotic factors may result in the progressive deposition of extracellular matrix and finally in the development of pulmonary fibrosis.
Results from a wide body of work indicate that the underlying mechanism for fibroproliferative diseases involves dysregulation and overproduction of certain cytokines. Among a number of cytokines investigated, a continued overproduction of TGF- ß appears to be at the heart of the molecular mechanism in the genesis of lung fibrosis: (a) TGF- ß is a potent modulator of a number of genes involved in organogenesis, tissue regeneration, and fibrosis, including genes for the ECM; (b) TGF- ß increases the production and/or activity of connective tissue growth factor and it stimulates biosynthesis of type I collagen, fibronectin and proteoglycans; (c) TGF-ß inhibits the expression of ECM protease; and (d) TGF- ß promotes the expression of tissue inhibitor of metalloproteinase . These actions of TGF- ß on the metabolism of ECM result in an excess accumulation of ECM proteins, a hallmark of fibrosis.
Th1 and Th2 Responses
Recent experimental and clinical studies suggest that a persistent imbalance in the expression of Th2 versus Th1 cytokines in the lung represents an additional possible mechanism for the progression of pulmonary fibrosis. In lung tissue of patients with IPF, the presence of Th2 cytokines predominated over the expression of Th1 cytokines, in particular interferon. Whereas Th2 cytokines (IL-4, IL-9, IL-13) activate fibroblasts and induce the production of extracellular matrix, Th1 cytokines (INF-?) have suppressive effects on fibroblast proliferation and the production of extracellular matrix such as collagen and fibronectin. It was therefore hypothesized that an imbalance between INF-? and the Th2 cytokines IL-4 and IL-13 that favours INF-? may be beneficial in inhibiting pulmonary fibrosis.
Conventional Line of Treatment
The standard treatment of IPF includes corticosteroids with or without cytotoxic agents such as colchicine, cyclophosphamide, or azothioprine. Treatment with corticosteroids results in objective improvement in only 10%-20% of patients, probably reflecting both the advanced stage of fibrosis at which the patients are brought to medical attention and the inability of corticosteroids to alter the non-inflammatory phase of the fibrotic processes. The combined treatment with corticosteroid and cytotoxic agents failed to affect the survival rate and appears to be invariably associated with overt systemic toxicity. Therefore, it is of utmost importance to develop new drugs that can be safely used for management of ILF.
Novel Approaches for the Treatment
Compounds Interfering With Collagen Biosynthesis. A variety of compounds have been developed that interfere with collagen synthesis at the transcriptional, translational, and posttranslational levels and with its degradation. But most of these compounds were considered either ineffective or too toxic for use in humans with IPF.
Taurine And Niacin. A multifaceted approach has been launched to blunt the fibrogenic effects of TGF- ß in the BL-rodent models of lung fibrosis as a preclinical assessment of possible therapeutic benefits against lung fibrosis in humans. This combination has been found to downregulate the Bleomycin-induced overexpression of both type I and type III procollagen mRNAs. The experimental evidence indicates that combined treatment with taurine and niacin ameliorates BL-induced lung fibrosis by down-regulating the BL-induced overexpression of TGF- ß mRNA at the transcriptional level.
Nf-B Antisense Oligonucleotides. It has been found that NF-ß is required for maximal transcription of many proinflammatory cytokines including TGF- ß and any strategies that block the activation of this transcription factor would have potential therapeutic benefits in many lung diseases including IPF. However, the drawbacks to antisense oligonucleotide therapy include limited stability due to rapid degradation by intracellular endonucleases, need for parenteral route of delivery, and systemic toxicity.
Pirfenidone. Pirfenidone is an investigational drug. It has been found that treatment with pirfenidone not only prevents but also can retard the progression of the lung fibrosis once it has started. The beneficial effects of pirfenidone against BL-induced lung fibrosis were demonstrated not only at the biochemical level but also at the functional level by a significant improvement in the vital, and inspiratory capacities of the lungs.
Interferon Gamma. Interferon gamma (INF-°) is a potentially attractive target molecule for therapeutic control of fibrosis because of its ability to regulate the functions of both macrophages and fibroblasts. INF-° diminishes the expression of, a profibrogenic growth factor produced by macrophages, and mast cells. In addition, it also inhibits fibroblast growth factors and a variety of neutrophil-derived cytokines, thereby suppressing fibroblast proliferation and collagen synthesis.
Anti-Tgf- ß Antibody, Tgf- ß Soluble Receptor. Experimental approaches that block the biological activities of TGF-ß attenuate the degree of fibrosis in animal models of lung fibrosis. For example, antibodies to TGF- ß significantly reduced the experimental lung and kidney fibrosis and a receptor antagonist to this cytokine also decreased accumulation of induced lung collagen.
Platelet-Activating Factor Receptor Antagonists. According to a number of studies, PAF appears to play a significant role in acute and chronic lung injury The findings that the PAF-receptor antagonist, WEB 2086, attenuated both BL- and amiodarone-induced lung fibrosis suggested the involvement of PAF in the pathogenesis of lung fibrosis.
Anti-Integrin Antibodies. Recent finding suggests that the integrin molecules are critical in both the normal physiology and pathology of the lung diseases and that the use of their antibodies offers a therapeutic potential for management of lung diseases including IPF in humans.
Nitric Oxide Synthase Inhibitors. Neutrophil- and macrophage derived nitrogen free radicals are suggested to play an important role in cytotoxicity and in the pathogenesis of many lung diseases. For example, increased levels of exhaled NO are associated with fibrosing alveolitis, asthma, and bronchiectasis. Furthermore, increased production of NO is also linked with hepatic fibrosis.
Thus interstitial lung fibrosis either of known or unknown etiology is a crippling disease that has defied any therapeutic modality to date. Generally, the standard treatment for IPF includes synthetic glucocorticoids with or without cytotoxic drugs like colchicine, cyclophosphamide, or azothioprine. This line of therapy has failed to improve the survival rate and appears to be invariably associated with overt systemic toxicity. But a no of new compounds developed in the last decade hav shown a new insight & opened new future prospects to deal effectively with the disease.
-- The authors are with Pharmacy group, Birla Institute of Technology and Science, Pilani