The Annals of Respiratory Medicine (AoRM), Vol I Issue 2

Cystic Fibrosis and Survival Beyond 40 Years

Cystic fibrosis (CF) is the most common life-shortening, genetically inherited condition in the Caucasian population. Despite the lack of a cure for the underlying cellular defect, median survival continues to improve and is currently approximately 38 years—children born today with CF are predicted to live beyond 50 years of age. The demographics are changing with the number of affected adults beginning to outnumber children, and there is an increasing cohort of adults who have survived beyond 40 years of age. The current article provides a summary of the latest research on older CF patients. The aim was to characterize patients with CF who have lived beyond 40 years and discuss factors contributing to survival. Studies show that CF long-term survivors are a heterogeneous group; the majority has features suggestive of the classic disease but a significant proportion (the late diagnosis group) has a specific definable phenotype. Determinants of survival are complex but include maintaining good health in childhood and optimal BMI, FEV, FVC, and no Pseudomonas aeruginosa at the time of transition from pediatric to adult care. It is important to identify the factors contributing to extended life in this cohort of survivors, as we can use this information to improve care for the entire CF population.

Age of Diagnosis and the Clinical Phenotypes of Adult Patients With Cystic Fibrosis

INTRODUCTION

Despite being a monogenic disease, Cystic Fibrosis has always been considered a clinical syndrome that may involve multiple organs. Over the past decades survival has improved and currently the median survival is approximately 38 years. Also, it is now recognized that there are patients with milder or atypical forms of CF, whose diagnosis is usually made at a later age.

OBJECTIVES

To summarize the clinical characteristics of late diagnosed CF patients in published cohorts and to discuss the possible explanations for the phenotype heterogeneity of the disease.

METHODS

A search in PubMed was conducted using the terms atypical cystic fibrosis, late survivors and cystic fibrosis, longevity and cystic fibrosis, and late diagnosis and cystic fibrosis. A total of 601 references in English were gathered and a review was undertaken to separate the articles that were related to the objectives.

RESULTS AND DISCUSSION

The following are the main characteristics of late diagnosed CF patients: the symptoms may start in infancy but the disease becomes clinically significant after 10 years old, the lung is the most affected single organ, pancreatic sufficiency is more common, borderline chloride sweat values are frequent, and ΔF508 mutation is less common. Few mutations are clearly associated with mild forms of CF. Individuals with similar mutations may have different clinical manifestations, suggesting that the variability in CF phenotype is influenced by CFTR genotype as well as by other genetic and environmental factors.

CONCLUSION

Clinicians should be aware of this less frequent form of the disease, with single organ manifestations and late presentation and diagnosis.

Rehabilitation in Critically Ill Patients

Prolonged stay in the hospital and difficult response to pharmacotherapy can often lead to severe complications in critically ill patients for muscle weakness, physical deconditioning, recurrent symptoms, mood alterations, and poor quality of life. Rehabilitation is a treatment able to expand short- and long-term management of chronic patients admitted to intensive care. Recovery of individual’s physical and respiratory functions are both aims of a rehabilitation course in this area.

The purpose of this review article is to resume a ‘‘state of art’’ of the currently available evidence for a rehabilitation strategy in critically ill patients, with a description of the main activities and techniques adopted.

Despite the use of several activities and techniques that have led to short-term beneficial effects on both pulmonary and physical functions, muscle retraining represents the most important evidence-based aspect of Intensive Care Unit-rehabilitation: indeed, it is associated with weaning success and helps patients to recover at their maximum at discharge

Endobronchial Ultrasound With Transbronchial Needle Aspiration (EBUS-TBNA) in Patients With Negative Results in Conventional Bronchoscopy

PURPOSE

The aim of this retrospective study is to evaluate the role of endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) in patients with enlarged lymph nodes or masses suspicious of malignancy and negative results on conventional bronchoscopy.

PATIENTS AND METHODS

From December 2008 to September 2010, 208 patients with enlarged lymph nodes or lesions suspicious of malignancy were examined by EBUS. Every patient underwent a CT-scan or PET-CT and conventional bronchoscopy with comprehensive tissue sampling. Only patients with normal tissue as a result of the examination and lesions that were not at reach for EUS were eligible for EBUS-TBNA.

RESULTS

In 96.6%, EBUS-TBNA was technically feasible. In 3.4%, target lesions were too small or beyond reach of the TBNA-system. Sensitivity reached 74% in procedures performed for staging of lung cancer. Futile surgery could be avoided in eight cases with positive samples from lymph nodes in the N2 or N3 position. In assumed lung cancer stage IIIB and IV, sensitivity was 81%. In cases with suspected tumors others than lung cancer, 80% sensitivity was achieved. In evaluation of recurrent disease, we obtained a sensitivity of 90%. EBUS-TBNA yielded 62% sensitivity in cases with suspected lung cancer stage I/II and 58% in assumed sarcoidosis. Sarcoidosis was the result of every sixth EBUS-TBNA carried out in patients with enlarged lymph node of unclear significance. The rate of complications was low (pneumothorax in one case, .49%).

CONCLUSION

We experience EBUS-TBNA as a valuable tool to add diagnostic accuracy and safety in a considerable number of patients in our daily clinical practice. The procedure is characterized by a low rate of complications. We were able to avoid surgical diagnostic procedures in a substantial number of cases.

Antigen Presentation by Dendritic Cells and the Practice of Immunotherapy

Allergen specific immunotherapy is the only disease-modifying modality available for allergy. Immunotherapy performed by allergists–immunologists is an effective means to control long-term morbidity and health- related costs for chronic diseases affecting a significant part of the general population. A wealth of new information is now requiring a reassessment of immunotherapy and its practice. In the field of physiology, antigen presentation by dendritic cells has shed new light on our understanding of the mechanisms of immunotherapy. In clinical practice, the sublingual administration of allergens has opened immunotherapy to an array of new applications and is promising to make immunotherapy available to large numbers of patients. The new developments, both scientific and clinical, are reviewed and a number of practical issues are addressed in view of the broadening of the practice of immunotherapy.

Impulse Oscillometry Testing in Chronic Cough in Children

INTRODUCTION

Chroni cough is a troublesome problem for children and the investigation to identify the underlying etiology is often inclusive.

OBJECTIVE

To assess lung function in children with chronic cough using impulse oscillometry (IOS).

METHODS

Sixty-seven children with chronic cough and 35 other children using age- and sex-matched controls were enrolled in this randomized control study. Patients and controls were subjected to IOS at the study entrance.

RESULTS

Airway resistance did not differ between cases and controls at baseline. Both cases and controls displayed significant reduction in resistance following bronchodilation; however, this was significantly more in cases (median ΔR5 Hz%: controls = − 17.5, range: −45.1 to −8.7, cases = − 6.4, range: −20.8 to −1.1, P<.001, median ΔR20 Hz%: controls = − 11.5, range:−37.6 to −5.4, cases: −1.8, range:−20.1 to −0.4, P<.001, median ΔX5 Hz%: controls: −23.1, range: −48.6 to −9.9, cases: −8.6, range: −34.2 to −2.4, P=.01, median ΔZ5 Hz%: controls = − 17.4, range: −44.8 to −9.8, cases: −6.8, range: −27.0 to −4.9, P<.001).

CONCLUSION

A proportion of patients with chronic cough tend to respond to bronchodilators by a significant reduction in airway resistance, as measured with IOS; an observation that supports an empirical trial of bronchodilators.

Spirometry and Respiratory Muscle Function During Ascent to Higher Altitudes

Alterations in lung function at a high altitude (HA) influence exercise capacity, exacerbate hypoxia, and possibly promote predisposition to high-altitude illness. The effects of the HA on lung function and the mechanisms underlying these alterations are currently under investigation. Here, we present a review of the documented alterations in pulmonary physiology and lung functions at the HA in humans. As the first interface between the environment and the body, the lung plays a vital role in the transfer of oxygen from air to blood. The respiratory system adapts to hypoxic stress at rest and during exercise at a HA when oxygen and carbon dioxide flux from tissues is greater. Hypoxic stimuli induce an increase in ventilatory drive and metabolic cost incurred by the respiratory muscles in addition to substantial dyspnea, which may limit exercise tolerance. The exchange of oxygen and carbon dioxide is significantly affected owing to the lower driving pressure for oxygen from air to blood and more rapid transit time of blood across the pulmonary capillaries. Diffusion limitation and ventilation/perfusion mismatch additionally occur, thereby accentuating hypoxemia. Studies on lung and respiratory muscle functions have disclosed a fluctuating course for spirometric measurements, respiratory muscle strength, and endurance at the HA. Specifically, transient increases in these parameters initially occur on ascent to each new altitude, followed by a gradual decline during the longer stay. Despite these restrictions, humans cope remarkably well in times of considerable stress from the hypoxic environment.

Influence of Atmospheric Parameters and Pollutants on Control of Breathing in Healthy Neonates

Pulmonary MALT Lymphoma: Clinical, Molecular, and Therapeutic Aspects

REVIEW ARTICLE


Marie Wislez^1, Raphaël Borie^2, Catherine Thieblemont^3, Marie-France Carette^4, Martine Antoine⁵ and Jacques Cadranel¹

Affiliations: ¹Service de Pneumologie et Réanimation, Centre de Compétence des Maladies Rares Pulmonaires, Hôpital Tenon, AP-HP, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, Paris, France; ²Service de Pneumologie, Hôpital Bichat, AP-HP, Université Diderot-Paris VII, Paris, France; ³Service d'Hémato-Oncologie, Hôpital Saint-Louis, AP-HP, Université Diderot-Paris VII, Paris, France; ⁴Service de Radiologie, Hôpital Tenon, AP-HP, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, Paris, France and ⁵Service d'Anatomie Pathologique, Hôpital Tenon, AP-HP, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, Paris, France

ABSTRACT

This general review aims to clarify the pathophysiological, diagnostic, prognostic, and therapeutic features of mucosa-associated lymphoid tissue (MALT) lymphoma.

MALT lymphoma is the most common type of pulmonary lymphoma. It develops in MALT and, in most cases, it is slow-growing and presents as an asymptomatic chronic alveolar opacity visible on radiography. The prognosis of the disease is excellent, and the current treatments available are discussed in this review (decision not to treat, surgery, single-agent chemotherapy).

Keywords: primary pulmonary lymphoma (PPL), mucosa-associated lymphoid tissue (MALT), chronic alveolar opacity.

Correspondence: Jacques Cadranel, Service de Pneumologie et Réanimation, Hôpital Tenon, 4 rue de la Chine 75970, Paris Cedex 20, France. Tel: +33 1 56 01 65 31; e-mail: jacques.cadranel@tnn.aphp.fr

Chemotherapy of Malignant Pleural Mesothelioma: Where Are We Now and Where Are We Going?

REVIEW ARTICLE


Gunnar Hillerdal

Affiliation: Department of Lung Medicine, Karolinska University Hospital, Stockholm, Sweden

ABSTRACT

The incidence of malignant pleural mesothelioma is increasing in most industrialized countries and even more so (though from low numbers) in developing countries. The prognosis is poor, but the median survival time has improved with modern chemotherapy, and some patients can live many years in good shape. The combination of pemetrexed and a platin compound is now the standard treatment all over the world with many studies confirming its efficiency. Unfortunately, there are no other drugs or combinations of drugs that have been compared to the standard treatment. Studies on such combinations are usually small, and even if they seem to have given positive results this could be due to the selection of patients. However, lacking alternatives they can be tried as second-line or when pemetrexed is contraindicated. These drugs include Vinorelbine, liposomized Doxorubicin, Gemcitabine, and others in various combinations. It is not possible to directly compare different studies, because the selection of patients varies too much. Many second-line studies are on-going and should be encouraged, and hopefully new active drugs can be found this way. Biological therapies have so far been a disappointment with this tumor, and in vitro effects can rarely be verified in clinical studies. Exceptions are a few promising studies with histone deacetylase inhibitors that are on-going. With the present very active research, more effective treatment options of malignant mesothelioma are likely in the future.

Keywords: malignant pleural mesothelioma, chemotherapy, review

Correspondence: Gunnar Hillerdal, Department of Lung Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden. Tel: +46-8-5177000; Fax: +46-8-332998; e-mail: gunnar.hillerdal@karolinska.se

An Update on Bronchodilator Treatment of Chronic Obstructive Pulmonary Disease (COPD)

REVIEW ARTICLE


Walter Vincken

Affiliation: Respiratory Division, University Hospital Brussels (UZ Brussel), University of Brussels (Vrije Universiteit Brussel), Belgium

ABSTRACT

Although the main characteristic of chronic obstructive pulmonary disease (COPD) is relentlessly worsening airflow limitation, many patients show some degree of reversibility and, more importantly, clinically relevant improvements in dyspnea, exercise capacity, and health status following the administration of a bronchodilator. The mechanism through which bronchodilators effect these improvements appears to be a reduction in hyperinflation both at rest and during exercise. Bronchodilators also consistently reduce exacerbations. As a result, bronchodilators have become the recommended cornerstone of maintenance treatment of COPD.

Three classes of bronchodilators are currently available: the oral methylxanthine theophylline, both short-acting (SA) and long-acting (LA) inhaled ß2-adrenergic receptor agonists (BA), and anticholinergics (AC) or muscarinic receptor antagonists (MA). The SA inhaled bronchodilators are still used for rescue treatment, but should, for maintenance treatment, be replaced by their LA counterparts for reasons of both efficacy and convenience. Evidence also advocates the introduction of LA inhaled bronchodilators early in the disease process. Among the available LA inhaled bronchodilators, the once daily LAMA tiotropium appears a safe, effective, and convenient choice to initiate maintenance treatment with, but the advent of equally effective and convenient once daily LABAs and LAMAs may offer clinicians a valid alternative. Furthering the debate as to which bronchodilator to start maintenance treatment with is somewhat superfluous, as the constant finding that a combination of bronchodilators acting through different mechanisms has at numerous times been shown to be superior and perhaps safer than treatments with a single bronchodilator class. Once-daily combinations of LAMA and LABA formulated into one single device are now under way and probably will become the preferred maintenance treatment for COPD patients. Finally, another important step forward in the treatment of COPD will be the development of inhalation devices delivering aerosols with optimal pulmonary deposition and equipped with features that facilitate their correct handling by the COPD patient.

Keywords: COPD, treatment, bronchodilators, inhalation

Correspondence: Walter Vincken, Respiratory Division, University Hospital Brussels (UZ Brussel), 101 Laarbeeklaan, 1090 Brussels, Belgium. Tel: +32 (0)2 4776841; Fax: +32 (0)2 4776840; E-mail: walter.vincken@uzbrussel.be

Pulmonary Arterial Pressure during Rest and Exercise (from Geneva, 1961 to Dana Point, 2008)

REVIEW ARTICLE

Gabor Kovacs and Horst Olschewski

Affiliation: Medical University of Graz, Division of Pulmonology, Graz, Austria


ABSTRACT

The first hemodynamic definition of pulmonary hypertension was introduced at a World Health Organization (WHO) meeting on Primary Pulmonary Hypertension in Geneva in 1973. Pulmonary hypertension was defined as mean pulmonary arterial pressure (mPAP) >25 mmHg at rest or >30 mmHg during exercise. This hemodynamic definition was broadly used by clinicians and researchers, and was adopted at upcoming world conferences in Evian 1998 and Venice 2003. At the last world conference in Dana Point in 2008, however, the hemodynamic definition was discussed again. According to the published literature, based on invasive measurements in healthy individuals, resting mPAP is 14.0±3.3 mmHg, is virtually independent of gender and geographical origin, and is only mildly influenced by posture and age. During exercise, however, mPAP is dependent on exercise level and age. The Dana Point statement defines the normal range of resting mPAP between 8 and 20 mmHg and pulmonary hypertension as resting mPAP >25 mmHg. As it may not be possible to define a single upper limit of normal mPAP fitting to all individuals and all exercise levels, the exercise part of the old definition of pulmonary hypertension was abandoned. Further studies are warranted to better determine the natural history of patients with mPAP between 20 and 25 mmHg and an out-of-proportion increase in mPAP during exercise.

Keywords: pulmonary hypertension, pulmonary arterial pressure, exercise, hemodynamic definition, normal

Correspondence: Gabor Kovacs, Medical University of Graz, Division of Pulmonology, Auenbruggerplatz 20, 8036 Graz, Austria. e-mail: gabor.kovacs@klinikum-graz.at

Talc Particle Size: Does it Influence the Acute Systemic Inflammatory Response in Talc Pleurodesis?

REVIEW ARTICLE


Eduardo H. Genofre, Francisco S. Vargas and Evaldo Marchi

Affiliation: Laboratory of Pleura Pulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil


ABSTRACT

Talc has been the most used agent worldwide for induction of pleurodesis. However, despite its popularity, wide availability, low cost, and high success rate, there is great concern about the adverse effects of intrapleural talc application. Among these, we highlight acute respiratory failure that can be potentially fatal. The mechanism by which talc pleurodesis produces local and systemic inflammatory response is not well known. It is speculated that the large variation in particle size and the presence of contaminants in talc composition may be responsible for the effects observed in clinical practice. Experimental studies have shown that talc of smaller particles (<5 µm) may migrate to several organs. In addition, the intense local inflammation induced by talc may promote the loss of integrity of the capillary barrier, allowing the free flow of inflammatory mediators between the pleural and the systemic compartments. Despite the proven efficacy of talc in producing pleurodesis, its safety is not absolute.

Keywords: Pleura, pleural effusion, pleurodesis, magnesium silicates, inflammation, inflammation mediators, talc

Correspondence: Eduardo Henrique Genofre, MD, PhD; Av. Lins de Vasconcelos, 1455–Ap 141–Bl 01–CEP 01537-001–Sao Paulo–SP–Brazil. e-mail: ehgenofre@uol.com.br; ehgenofre@me.com

Gender Differences in COPD Mortality: A Descriptive Review of the Literature

REVIEW ARTICLE

Juan P de Torres^1, Ciro Casanova² and Bartolome R Celli³

Affiliations: ¹Pulmonary Department, Clinica Universidad de Navarra, Pamplona, Spain; ²Pulmonary Department, Hospital Ntra Sra de Candelaria, Tenerife, Spain; and ³Pulmonary Department, Brigham and Women Hospital, Harvard Medical School, Boston, Massachusetts, USA


ABSTRACT

Chronic obstructive pulmonary disease (COPD) will be one of the leading causes of death in the near future. Traditionally a disease associated with the male gender; in the last decades COPD has become an increasing problem among women. In the United States as well in other developed countries like Canada, the United Kingdom, and Finland, the number of cases, hospitalizations, and deaths among women have exceeded those among men. Little is known about gender differences in mortality in COPD patients. Lately, a few studies have challenged the knowledge that women with the disease have a better survival than men. This article intends to review, from a gender perspective, factors affecting COPD survival and the existing literature about gender differences in mortality.

Keywords: gender, COPD, mortality

Correspondence: Juan Pablo de Torres, Pulmonary Department, Clinica Universidad de Navarra, Av Pío XII, 36 CP 31008, Pamplona, Spain. Tel: 0034 948255400; Fax: 0034 296500; e-mail: jupa65@hotmail.com

Inhaled Corticosteroids and Lung Cancer Chemoprevention in Chronic Obstructive Pulmonary Disease Patients: What Should We Make of What We Observe?

Review Article


A Victor Kiri

Affiliation: Department of Peri Approval Clinical Excellence, PAREXEL International, Uxbridge, UK


ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide with an estimated 2.75 million deaths in 2000 (fourth leading cause of death). The lung is a major site of cancer in the world today, representing about 13% of all new cancers. Epidemiological data indicate that COPD patients are at increased risk of cancer, especially lung cancer, and COPD is recognized as a major risk factor for lung cancer independent of the effect of smoking. Both diseases incur significant healthcare and societal costs, and smoking cessation remains the most effective control for reducing the risk of developing either disease. Although no randomized controlled trial has demonstrated an effective therapy against COPD mortality, many trials have reported positive results for inhaled corticosteroids (ICS) and long‐acting bronchodilators (LABA) on lung function improvement, reduction in exacerbation, and reduction in health‐related costs. Indeed, observational studies have suggested some COPD survival benefits from the combined use of both ICS and LABA and, more notably, a few others have also found evidence of reduction in lung cancer risk among COPD patients exposed to ICS. The possibility that ICS may possess such chemopreventive effects in COPD deserves better attention.

Keywords: chronic obstructive pulmonary disease (COPD), lung cancer, chemoprevention, inhaled corticosteroids, peripheral adenocarcinoma, squamous cell carcinoma
Correspondence: Victor A Kiri, Department of Peri Approval Clinical Excellence, PAREXEL International, Uxbridge, Middlesex UB8 1LZ, UK. Tel: (44)‐1895–614760; Fax: (44)‐1895–614277; e‐mail: Victor.Kiri@PAREXEL.com

The Relation between Right‐to‐Left Shunt and Migraine: Focus on Pulmonary Arteriovenous Malformations

Review Article


WF Marco van Gent¹, HAM Michiel van Helden¹, J Johannes Mager² and C Martijn Post¹

Affiliations: Department of ¹Cardiology and ²Pulmonology, St Antonius Hospital, Nieuwegein, the Netherlands


ABSTRACT

Migraine is a common and disabling disorder. Pulmonary arteriovenous malformations (PAVMs) cause a right‐to‐left shunt (RLS). An increased prevalence of migraine, particularly migraine with aura (MA+), has been shown in patients with a RLS of both pulmonary and cardiac origin. The prevalence of PAVM in patients with hereditary hemorrhagic telangiectasia (HHT) is 15–45%. Therefore, the HHT population provides a unique opportunity to study the RLS–migraine hypothesis. Embolization of PAVMs might reduce the prevalence of migraine, and an association between PAVM in HHT patients and MA+ was shown recently in a prospective study. The current review focuses on the evidence of a real association between an intrapulmonary RLS and migraine, and summarizes the possible underlying pathogenesis.

Keywords: pulmonary arteriovenous malformations, right‐to‐left shunt, migraine, hereditary hemorrhagic telangiectasia, patent foramen ovale
Correspondence: M C Post, Department of Cardiology, St Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, the Netherlands. Tel: (31)‐30‐6099111; Fax: (31)‐30‐6092274; e‐mail: m.post@ antoniusziekenhuis.nl

Assessment of Interstitial Lung Disease in Systemic Sclerosis and Impact on Disease Progression and Outcomes

Review Article


E Koumakis , A Kahan  and Y Allanore

Affiliation: Paris Descartes University, Rheumatology A Department, Cochin Hospital, APHP, 75014 Paris, France


ABSTRACT

Interstitial lung disease (ILD) has emerged as a major cause of mortality in systemic sclerosis (SSc), representing about 30% of SSc‐related deaths. ILD occurs in up to 75% of patients with SSc, but progresses to severe restrictive lung disease in only about 10–15% of these patients. Histopathologic lesions are characterized in most cases by non‐specific interstitial pneumonia. Risk factors for the occurrence of pulmonary fibrosis include diffuse cutaneous SSc and anti‐topoisomerase I antibodies. ILD often remains asymptomatic, and the presence of symptoms often indicates advanced lung disease. Therefore, early detection of ILD is a major concern in SSc patients. The diagnosis and follow‐up of SSc‐related ILD (SSc‐ILD) is based essentially upon non‐invasive examinations including pulmonary function tests and high‐resolution pulmonary computed tomography scan (HRCT). The utility of outcome measures for pulmonary involvement in SSc has been assessed by the OMERACT filter, according to several criteria (truth, discrimination, and feasibility). Risk factors for the deterioration of lung function include low baseline forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) values, and initial HRCT abnormalities. This article details and summarizes the available data on prognostic factors for SSc‐ILD and the association of lung involvement with disease progression in SSc.

Keywords: systemic sclerosis, interstitial lung disease, pulmonary function tests, computer tomography (CT) scan
Correspondence: Yannick Allanore, Service de Rhumatologie A, Hôpital Cochin, Université Paris Descartes, 27 rue du Faubourg Saint‐Jacques, 75014 Paris, France. Tel: (33)‐1‐58‐41‐25‐72; Fax: (33)‐1‐58‐41‐26‐24; e‐mail: yannick.allanore@cch.aphp.fr

Role of Leukotriene B4 Receptor Antagonist in Pulmonary Fibrosis

Review article


Takehiro Izumo, Mitsuko Kondo, Naoki Arai and Atsushi Nagai

Affiliation: First Department of Medicine, Tokyo Women’s Medical University School of Medicine, Shinjuku-ku, Tokyo, Japan


ABSTRACT

Leukotrienes (LTs) are important chemoattractants for leukocytes and play a pivotal role in the pathogenesis of inflammatory and immune disease, and recent evidence suggests that LTs also play an important role in pulmonary fibrosis. The synthesis of leukotriene B4 (LTB4) and cysteinyl leukotriene (cysLT) is catalyzed by 5‐lipoxygenase. Elevated levels of LTB4 in bronchial alveolar lavage fluid have been reported in allergic diseases and pulmonary fibrosis. Recent reports using LTB4 receptor (BLTR) antagonists have revealed that ligation of BLTR by LTB4 is important for the activation and recruitment of inflammatory cells including neutrophils, eosinophils, monocyte/macrophages, and T cells to inflamed tissues in inflammatory diseases. Although it is about 30 years since LTB4 was discovered in 1979, recent research about BLTR antagonists has revealed the important roles of the LTB4/BLTR pathway in the pathophysiology of pulmonary diseases, such as bronchial asthma and pulmonary fibrosis. We reported recently that BLTR antagonists inhibited the development of bleomycin‐induced pulmonary fibrosis in mice by decreasing the inflammation and altering transforming growth factor β, interleukin (IL)‐6, IL‐13, and interferon γ. Current therapy for pulmonary fibrosis is ineffective, and the disease has a poor outcome and is associated with severe morbidity. Corticosteroid therapy for pulmonary fibrosis is not effective and does not prevent progression. Targeting of the LTB4/BLTR pathway may be an important strategy in the treatment of pulmonary fibrosis.

Keywords: pulmonary fibrosis, leukotriene B4, leukotriene B4 receptor (BLTR), leukotriene B4 receptor antagonist, cysteinyl leukotriene
Correspondence: Takehiro Izumo, First Department of Medicine, Tokyo Women’s Medical University, School of Medicine, 8‐1 Kawada‐cho, Shinjuku‐ku, Tokyo, 162‐8666, Japan. Tel: (81)‐3‐3353‐8111; Fax: (81)‐3‐5379‐5457; e‐mail: drtake@s6.dion.ne.jp