Current Respiratory Medicine Reviews - Volume 9, Issue 5, 2013

Vitamin D deficiency, a worldwide epidemic has been vastly studied in the last years and was found associated with different medical conditions varying from cancer to immune diseases. In this review article we have proposed that vitamin D is highly correlated with two chronic respiratory diseases, Asthma and COPD using population based and biological studies. The mechanism linking between these respiratory diseases involves numerous agents ranging from cell signaling pathway to anti-inflammatory cytokines. In addition, the role of vitamin D supplementation seems promising especially in the management of Asthma disease.

Statins are a group of drugs designed to lower cholesterol by inhibiting the enzyme HMG-CoA reductase. Statins have been shown to exhibit anti-inflammatory effects and have been suggested to be effective in some respiratory diseases. The aim of this review is to describe possibly mechanism of actions and effects of statins in respiratory diseases. Statins effects in respiratory diseases have been suggested to be related to decreases anti-inflammatory cells and proteins, decrease adhesion and migration of inflammatory cells, reduction of oxidative stress in the lung and anti-fibrotic properties. In asthma and COPD, statins have been suggested to have some synergistic effect with bronchodilators and antiinflammatory drugs. In scleroderma, anti-fibrotic, immune-modulating, and vasodilatory effects of statins are potentially beneficial as have been demonstrated by some studies. Statins have been shown to decrease TGF- β which is one of the key mediators in bronchiolitis obliterans but clinical investigation is still needed to show this effect in vivo. Clinical trials have failed to show beneficial effect of statins in idiopathic pulmonary fibrosis and in hypersensitivity pneumonitis and organizing pneumonia statins have been even suggested to be a cause. More investigation is needed for understanding the full clinical effects of statins in respiratory diseases.

The nitrogen-containing compound, colchicine, has been used medicinally for millennia. It was first isolated from the plant Colchicum autumnale, by the French chemists P.S. Pelletier and J. Caventon. Today, colchicine is primarily used for the treatment of gout and auto-inflammatory diseases, such as familial Mediterranean fever (FMF), but it has been also investigated for its therapeutic utility in a number of respiratory diseases such as asthma, chonic obstructive pulmonary disease and idiopathic pulmonary fibrosis. While colchicine has shown some promise as an adjuvant to corticosteroid treatment, the benefit of the drug remains to be elucidated. The lack of serious adverse effects of oral colchicine at therapeutic levels should ease the design of more specific trials.

Methotrexate (MTX), a folate analogue anti-metabolite, has long been recognized for its beneficial chemotherapeutic and immuno-modulatory effects and has therefore been used in the past 6 decades to treat a variety of malignant and autoimmune disorders. MTX has emerged in the past 2 decades, as a potential drug in the management of patients with chronic pulmonary diseases including airway hypersensitivity disorders, granulomatous diseases, and auto-immune disorders affecting the lung interstitium. Although bearing a unique hematologic and hepato-pulmonary toxicity profile, some dosing strategies and monitoring guidelines have been developed in order to ensure a safe utilization. The pulmonary toxicity has a variable clinicopathological presentation spectrum and a myriad of etiologic factors have been implicated in the pathophysiologic mechanisms including infectious, immunological, and direct toxic effects. In the hereby article, we present a brief review of the drug's of mechanism of action, dosing techniques and main side effects, after which MTX's role in the treatment of asthma, sarcoidosis and vasculitides involving the lung is discussed. The use of its salvage drug, leucovorin, is also reviewed.

Macrolide are antibiotics active against Gram-positive bacteria, but these agents exhibit also an antiinflammatory activity with several mechanisms suggested. The benefit of macrolides in the treatment of pulmonary disease is well known, although in some cases there is a lack of understanding of the exact pathway in which they contribute to the therapy. Several studies have examined the benefits of macrolide treatment on patients with chronic asthma. Possible modes of action include direct anti-bacterial activity, specifically against Chlamydia pneumonia, decreased metabolism of steroid drugs, and a modulation of the immune response. Some of the studies show overall asthma symptoms improvement, reducing corticosteroid requirements and an increase in FEV1. Cystic Fibrosis patients using macrolide therapy had fewer pulmonary exacerbations, delayed onset of the first pulmonary exacerbation, and a reduced need for additional antibiotic therapy. Low dose erythromycin treatment (less than a therapeutic dose for bacterial infection) in patients with diffuse panbronchiolitis showed significantly survival increase, suggesting that the anti-inflammatory properties of the antibiotic are responsible for the improvement. This article will review the use of macrolide therapy in various lung diseases.

Interferons (IFNs) are a subclass of lymphocyte-released cytokines that interfere with intracellular viral replication. These drugs are classified into three groups: IFN type 1 (IFN-α, IFN-β, and IFN-ω), IFN type 2 (IFN-γ), and IFN type 3 (IFN-λ). Despite numerous trials, IFN therapy has yet to conclusively demonstrate superiority in the treatment of various pulmonary diseases. In addition to the FDA-approved and ongoing investigational uses for IFN therapy, there is a debate regarding the appropriate dosage of these agents. A retrospective literature review is moving experts towards low-dose therapies in nearly every application of IFN therapy. It is speculated that known and unknown toxicity may limit the beneficial effects of IFN therapy.

N-acetylcysteine (NAC), the N-acetyl derivative of the amino acid cysteine, is perhaps best known for its wide use in the treatment of acetaminophen (paracetamol) toxicity, but it has been investigated for the treatment of myriad conditions. In this article we will review the uses of NAC in pulmonary diseases, the mechanism of action dosing, side effect profile and clinical implications in regard to COPD and idiopathic pulmonary fibrosis. One of the main targets of NAC is Inflammation and oxidative stress that are important factors in the pathogenesis of many chronic inflammatory lung disorders. While it is logical to conclude that the administration of antioxidants such as NAC will provide a mode of treatment for said conditions by targeting antioxidant-oxidant imbalance [8] and although the theory supporting the use of antioxidants is sound, it may not necessarily translate into clinical benefit. Based on the available evidence it is unlikely that mucolytics such as NAC will drastically affect symptoms, exacerbations or disease modification in COPD.

Gold salts have been introduced as therapeutic agents in the late 19th century. The three gold salts approved for medical therapy auranofin, aurothiomalate, and aurothioglucose were shown to induce anti-inflammatory and immunosuppressive states via a myriad of mechanisms and used to be a mainstay of therapy for rheumatoid arthritis as well as other rheumatic and collagen vascular diseases before being supplanted by other less toxic agents. The research into the role of gold compounds in therapy of pulmonary disease have focused on asthma and demonstrated a significant anti-inflammatory effect as well as a mild steroid-sparing effect mainly in Japanese patients. These effects were offset by a wide array of adverse reactions, notably dermatological, hematological and renal effects. The main pulmonic adverse effect associated with gold therapy is interstitial pneumonitis which can present with an acute, subacute and chronic course. The role of gold salts in the therapeutic arsenal of COPD and interstitial lung diseases is less established. Recently published studies have investigated the role of aurothiomalate as an inhibitor of non-small cell lung cancer oncogene PKC iota.

It is well established that inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD), asthma and interstitial lung diseases (ILD). A wide variety of triggers may induce the recruitment and activation of inflammatory cells in the airways and stimulate both innate and adaptive immune mechanisms. Airway inflammation is implicated in many of the clinical characteristics of both entities. Basal levels of inflammatory mediators are often elevated during exacerbations, as a manifestation of the underlying process. Idiopathic pulmonary fibrosis (IPF) is a life-threatening variant of ILD. In IPF chronic injury and excessive apoptosis of alveolar epithelial type II (AECII) cells occurs, leading to permanently perturbed epithelial homeostasis. Treatment modalities aiming to attenuate epithelial injury are currently in early pre-clinical development and may reach the clinical arena in only a few years. This review will focus on four drugs: pirefendinone, penicillamine, chloroquine, and chlorambucil. These agents have demonstrated immunomodulatory effects through different pathways. We will describe their mechanisms of action, side effects, and their potential use in various pulmonary diseases based on available clinical data. Unfortunately their current use is restricted due to limited efficacy, paucity of randomized clinical trials, and side effects resulting in a relatively narrow therapeutic index. Future trials will determine their exact role in the management of the various pulmonary diseases under discussion.

Cyclosporine, also known as cyclosporine A (CsA), works primarily as an immunosuppressant by the inhibition of interleukin and immunomediator synthesis. It was first approved for clinical use for the prevention of transplant rejection. The objective of this review is to describe the use of CsA in lung illnesses, emphasize the disadvantages due to the risk of side effects such as immunosupression and nephrotoxicity, and pinpoint where CsA is most useful in today's evolving treatment protocols. CsA is available in both modified and unmodified forms, modification of the drug improves the oral bioavailability. Its administration is limited mainly due to nephrotoxicity and immunosuppression. Patients who receive high doses, particularly transplant patients, are prone to opportunistic infections. Clinically it has several respiratory uses, some of which are still under investigation. One of the main uses is to prevent rejection in lung transplants, which manifests as bronchiolitis obliterans. CsA is used as part of a triple regimen in lung transplant patients, which targets the T-cell role in lung rejection. It is currently under investigation for use via aerosol delivery for prevention of chronic rejection. Other known clinical uses are in inflammatory and infiltrative lung diseases. In cases of asthma it is an option as a steroid sparing treatment, and remission therapy in cases of Idiopathic Pulmonary Fibrosis (IPF) refractory to pulse therapy. In cases of Interstitial Lung Diseases (ILD) CsA was preferred where infiltration was of a predominately cellular type as opposed to fibrotic type. Survival benefit was shown in case reports of Wegener’s granulomatosis, Churg-Strauss syndrome, and arthritis associated interstitial lung disease, especially by achieving steroid sparing effect.