Current Respiratory Medicine Reviews - Volume 5, Issue 1, 2009

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Pulmonary fibrosis is involved in several respiratory diseases such as idiopathic interstitial pneumonias, druginduced pulmonary disease, occupational or environmental pulmonary disease and collagen vascular disease, and leads to systemic fatal damage in some cases. Several cytokines, inflammatory mediators, and growth factors play a complicated role in the progression of fibrosis, resulting in difficulty in specific therapy to overcome the disease. Among those mediators, inducible cyclooxygenase (COX)-2-dependent prostaglandin (PG) E2 exhibits inhibitory effects for fibroblast proliferation and collagen synthesis. Induction of COX-2 expression associated with increased production of PGE2 was observed in bleomycin-induced pulmonary fibrosis in rat. The inhibitory effects could be mediated via the EP2 and/or EP4 receptors coupled to elevation of cAMP. Fifteen-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), which is a derivative of PGD2 by non-enzymatic hydrolysis and an anti-inflammatory PPAR γ ligand, has been focused in asthma, chronic obstructive pulmonary disease, acute lung injury and pulmonary fibrosis. Attenuation of pulmonary fibrosis by 15d-PGJ2 has confirmed by introduction of cells retrovirally transfected with PGD2 synthase cDNA. Administration of PGD2 synthaseexpressing cells to mice suppressed the fibrosis with reduced expression of fibrogenic growth factors. Thus, manipulation of anti-fibrogenic prostaglandins, PGE2 and 15d-PGJ2 may contribute to the development of specific therapy for pulmonary fibrosis.

The integration of knowledge concerning the regulation of metallothionein (MT) with research on its proposed functions is necessary to clarify how MT affects cellular processes. MT expression is induced/enhanced in various tissues by a number of physiological mediators through several response elements in the MT gene promoter. The cellular accumulation of MT depends on the availability of cellular zinc derived from the diet. MT modulates: 1) the binding and exchange/ transport of heavy metals such as zinc, cadmium, or copper under physiological conditions and cytoprotection from their toxicities, and 2) the release of gaseous mediators such as hydroxyl radicals or nitric oxide. In addition, MT reportedly affects a number of cellular processes, such as gene expression, apoptosis, proliferation, and differentiation. Given the genetic approach, the apparently healthy status of MT-deficient mice argues against an essential biological role for MT; however, the molecule may be critical in cells/tissues/organs in times of stress, since MT expression is also evoked/enhanced by various stresses. In particular, because metallothionein (MT) is induced by inflammatory stress, its roles in inflammation are implied. Also, MT expression in the lung can be enhanced by inflammatory stimuli, suggesting that its expression correlates with inflammatory lung diseases. In this paper, we review the role of MT of various inflammatory conditions in the lung.

Low dose methotrexate (MTX) is used frequently in a wide variety of conditions. This includes rheumatological conditions such as rheumatoid arthritis (RA) and non-rheumatological conditions such as inflammatory bowel disease. One of the most serious although infrequent side effects of low dose MTX is MTX induced pneumonitis (MTX-P). The latest literature on epidemiology, risk factors, pathophysiology and clinical features of MTX-P will be critically reviewed and highlighted. This review will pay special attention to diagnostic criteria, high resolution computerised tomography (HRCT) scan findings, and when to consider bronchoalveolar lavage (BAL) and lung biopsy. We propose the 2008 diagnostic criteria adapted from existing criteria. We will also discuss the new issue of interstitial lung disease (ILD) in patients receiving both methotrexate and anti-TNF therapy.

Statins being the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are potent inhibitors of the key enzyme on cholesterol biosynthesis. However, considerable experimental and clinical evidence have shown that statins have pleiotropic effects on respiratory and cardiovascular systems that are beyond their cholesterol-lowering properties. Statins inhibit an early step in the cholesterol biosynthetic pathway. They also inhibit the synthesis of isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are involved in posttranslational modifications of small signaling molecules such as the Rho GTPases. Inhibition of RhoA geranylgeranylation by statins results in a wide range of cellular functions, such as cell migration, proliferation, and apoptosis. These processes may explain well immunosuppressive and immunomodulatory properties of statins. Recently, rising evidences suggested that RhoA/Rho-kinase pathway was essentially involved in various models of pulmonary hypertension and statins effectively ameliorated pulmonary hypertension. Interaction in Rho/Rac also leads to fibroblast apoptosis and reduction of TGF-dependent fibrogenesis. This indicates the potential of statins in halting progression of lung fibrosis. These properties, however, are not proven enough in a human clinical trial and request further clinical trails, to check whether animal data could be translated directly to humans. This paper reviewed the role and mechanism of action in two pathophysiological states of lungs: pulmonary fibrosis and pulmonary arterial hypertension. And a special emphasis was put on the indication and limitation of statins therapy in these diseases.

Alcohol abuse is a systemic disorder and increases the risk of lung injury. After ingestion, alcohol freely diffuses from the bronchial circulation directly through the ciliated epithelium where it vaporizes as it moves into the conducting airways. Some of vaporized alcohol can deposit back into the airway lining fluid and results in repeated exposure of the airway epithelium to high local concentrations of alcohol. Chronic alcohol ingestion is associated with increased renin-angiotensin system, induces oxidative stress through angiotensin (Ang) II stimulated NADPH oxidase expression and activity, and superoxide production. Alcohol metabolism within the lung through the cytochrome P 450 system may also be sufficient to exert significant oxidative stress. Alcohol inhibits the expression of GM-CSF and impairs immune system. Chronic ingestion of ethanol altered cellular functions and viability such as decreased surfactant processing, decreased barrier integrity, increased sensitivity to cytotoxin-induced apoptosis in vitro and in vivo in alveolar type II cells, and decreased phagocytosis of microorganisms in alveolar macrophages. The lung becomes more susceptible when a second hit such as sepsis occurs. Though dietary supplementation with glutathione precursors or selective Ang II type 2 receptor inhibition limits lung injury in animal model, the most attractive candidate for treating the alcoholic lung in the acute setting is recombinant GM-CSF. Whether any of these therapeutic strategies will prove to be effective in decreasing the consequences of alcohol abuse on acute pulmonary diseases is at present unknown.

Conventional treatment of pulmonary arterial hypertension (PAH) includes oxygen supplementation, calcium channel blockers, anticoagulation, digoxin, and diuretics. Calcium channel blockers have little or no effect on the majority of patients with moderate or severe PAH. Apart from the intravenous prostacyclin which remains the gold standard treatment for this life-threatening entity, newer drugs such as prostacyclin analogues, endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors alone or in combination administered by means of different routes have been shown to improve oxygenation, hemodynamics, exercise tolerance, symptoms, and quality of life. Based on current WHO classification there are 5 groups of pulmonary hypertension. In this article, PAH is used exclusively for Group 1 of WHO classification. There are currently six FDA approved therapies for PAH. However, all these therapeutic agents and approaches have not offered yet a cure of PAH. This review article presents the recent advances in the management of PAH.

Pulmonary hemorrhage (PH) is a life-threatening complication in systemic lupus erythematosus (SLE) occurring in 0.5% to 5.7% of lupus patients. PH is more common in women. The mean age at onset is around 30 years. Most have an established diagnosis of SLE but in approximately 20% PH occurs at onset of diagnosis. PH should be suspected in lupus patients presenting new pulmonary infiltrates, a rapid decline in hemoglobin level and any of the following: hemoptysis, dyspnea, hypoxemia, paradoxical increase of carbon monoxide diffusing capacity, or bronchoscopic evidence of hemorrhage. Radiographic abnormalities are non-specific but commonly show alveolar infiltrates. Pulmonary infiltrates are usually bilateral, perihilar or basilar with sparing of apices. PH usually occurs in patients with active lupus presenting extra-pulmonary manifestations, the most common being renal involvement. Hematologic abnormalities, central nervous system involvement, mucocutaneous manifestations, elevated anti-dsDNA antibodies and low C3 and C4 complements are also frequently seen. PH can lead to a prompt death; thus, early diagnosis and aggressive therapy are crucial. Treatment includes high-dose corticosteroids, cyclophosphamide and plasmapheresis. Improved survival rates have been reported lately, which could be related to better management of ventilatory support and the use of broad-spectrum antibiotics, together with timely and aggressive therapy.

Antibodies mediate humoral immune responses and play key roles in the defense of viral infection by the recognition, neutralization, and elimination of viruses from the circulation. For the prevention of respiratory syncytial virus (RSV) infection, the pooled human plasma has been harvested and successfully developed as a prophylactic polyclonal RSV hyperimmune globulin, RespiGam (RSV-IGIV; MedImmune, Gaithersburg, MD). The success of RSV-IGIV validated the immunoprophylaxis approach for RSV prevention and led to the development of Synagis (palivizumab; MedImmune, Gaithersburg, MD), a humanized monoclonal antibody (mAb) that binds to the RSV F protein. Palivizumab is a potent anti-RSV mAb that is about 50-fold more potent than RSV-IGIV, and since obtaining regulatory approval in 1998 it has been used extensively to help prevent severe RSV disease in high-risk infants and children. However, a very small number of patients receiving the drug do not appear to be adequately protected. To further improve protection against RSV, we have applied a directed evolution approach to enhance the binding of palivizumab to F protein by assessment of both on and off rates. These efforts have yielded a more potent second-generation mAb, motavizumab, which is currently under study in phase III clinical trials. Most recently, a third generation mAb, Numax-YTE, has been generated with the intent to extend the half-life in serum of the mAb in humans. The aim of this review is to evidence the pharmacokinetic and pharmacodynamic characteristics of these drugs and to evaluate their efficacy.

Diaphragmatic pacing, also known as electrophrenic respiration or phrenic pacing has been used for quite some time in patients with respiratory failure due to diaphragmatic paralysis. We present a case of patient with respiratory insufficiency due to unilateral phrenic nerve injury as a result of radiation therapy for breast cancer. The patient had a diaphragmatic pacer inserted, with significant recovery on her symptoms. Three years after this procedure, the patient recovered her phrenic nerve function, and this was confirmed by nerve conduction study.

Staphylococcus aureus is a common human pathogen, and over the past 90 years has been increasingly recognized as an important cause of pneumonia. The epidemiology of staphylococcal pneumonia has changed over this time period, and S. aureus is now a frequent cause of both community-acquired and hospital-acquired pneumonia including ventilator- associated pneumonia. This article reviews the important changes in the epidemiology and microbiology of S. aureus, the clinical features of S. aureus pneumonia, and considerations in antibiotic therapy for this disease.