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T Cell Cytokine Production in Childhood Asthma Pp.1-6
Vanessa G. Brown and Madeleine Ennis
[Abstract] [Full text article]

Pulmonary Tuberculosis in Various Gene Knockout Mice With Special Emphasis on Roles of Cytokines and Transcription Factors Pp.7-13
Isamu Sugawara, Hiroyuki Yamada and Ruiru Shi
[Abstract] [Full text article]

Chemokines and their Receptors as Targets for the Treatment of COPD Pp.15-32
Suzanne L. Traves and Louise E. Donnelly
[Abstract] [Full text article]

Apoptosis in COPD Pp.33-41
Sandra Hodge, Greg Hodge, Mark Holmes and Paul N. Reynolds
[Abstract] [Full text article]

Interleukin-1, Neutrophil Elastase, and Lipopolysaccharide: Key Pro-Inflammatory Stimuli Regulating Inflammation in Cystic Fibrosis Pp.43-67
Tomas P. Carroll, Catherine M. Greene, Clifford C. Taggart, Noel G. McElvaney and Shane J. O’Neill
[Abstract] [Full text article]

Bone Marrow-Derived Cells in the Pathogenesis of Lung Fibrosis Pp.69-76
Bethany B. Moore, Victor J. Thannickal and Galen B. Toews
[Abstract] [Full text article]

Pulmonary Surfactant-Update on Function, Molecular Biology and Clinical Implications Pp.77-84
Joanna Floros, David S. Phelps, Ulrich Pison and Roger Spragg
[Abstract] [Full text article]

Severe Acute Respiratory Syndrome (SARS): A Brief Review With Exploration of the Outcomes, Prognostic Factors and Sequelae Pp.85-92
Johnny W.M. Chan and Chun Kong Ng
[Abstract] [Full text article]

Lung Remodeling in Interstitial Pneumonia: A New Molecular Target of Pulmonary Fibrosis Pp.93-101
Mitsuhiro Sunohara and Hajime Takizawa
[Abstract] [Full text article]

Clinical Potencies of Glucocorticoids: What do we Really Measure? Pp.103-108
Emile F.L. Dubois
[Abstract] [Full text article]

Abstracts

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T Cell Cytokine Production in Childhood Asthma
Vanessa G. Brown and Madeleine Ennis
[Full text article]

A recent asthma audit demonstrated that, 1.4 million children (one in eight) in the UK today are receiving treatment for their asthma, and that this figure has increased six-fold in the last 25 years. The chronicity of asthma has been associated with cytokine-mediated inflammation, in particular from T helper 1 (Th1) and T helper 2 (Th2) cells. Over the past 10 years, a number of studies have tried to unravel the role of T cell cytokines in childhood asthma, as there may well be differences between childhood and adult asthma. Research in this area has been hampered by ethical and practical difficulties. Although a number of studies use whole or separated blood for investigative purposes, the use of T cells obtained from the airways, obtained by bronchoalveolar lavage (BAL), or sputum may be more representative of in vivo cytokine expression. A large body of evidence suggests, that Th2 cytokines are upregulated in paediatric asthma. However, a number of more recent publications propose that Th1 cytokines may also have inflammatory effects in childhood asthma. In particular, IFNγ’s role in childhood asthma has been clearly documented in studies, from both blood and BAL. Such reports have questioned the concept of the Th1/Th2 imbalance in such childhood asthma. This review will discuss the current findings on cytokine production from T cells in children with atopic asthma, and attempt to unravel the cytokine complexities in childhood asthma.

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Pulmonary Tuberculosis in Various Gene Knockout Mice With Special Emphasis on Roles of Cytokines and Transcription Factors
Isamu Sugawara, Hiroyuki Yamada and Ruiru Shi
[Full text article]

The technique of gene targeting (knockout) has swept through biomedical research. Cytokine research has been revolutionized by knockouts and since then this technique has been widely utilized in various research fields including immunological, inflammation research and human disease model. This paper focuses on knockout mice in tuberculosis research among many infectious diseases. We have generated several knockout mice for inflammation research. After we infected various kinds of knockout mice suffering from Mycobacterium tuberculosis by aerosol infection, we investigated the roles of cytokines and transcription factors that regulate cytokines. We used knockout mice lacking IFN-γ, TNF-α, IL-18, IL-1 α/β, IL-4, IL-1 type 1 receptor, NF-IL6, TLR-2, TLR-6, interferon regulatory factor-1 (IRF-1), NK-κB p50, signal transducer and activator of transcription (STAT)1, STAT4, NKT cells and MyD88 genes in our experimental tuberculosis research. M. tuberculosis-infected knockout mice displayed various histopathologies depending on the degree of importance of the molecules in defense against tuberculosis. IFN-γ, TNF-α, IRF-1, NF-IL6, NF-κB p50, STAT1 and STAT4 knockout mice succumbed to M. tuberculosis infection over time. The results indicate that these molecules play major roles for defense against tuberculosis. These knockout mice are essential for investigating their roles in experimental tuberculosis.

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Chemokines and their Receptors as Targets for the Treatment of COPD
Suzanne L. Traves and Louise E. Donnelly
[Full text article]

Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory condition, characterized by progressive, irreversible airflow obstruction. The major risk factor for development of COPD is cigarette smoking, and the disease is predicted to become the 3^rd leading cause of death by 2020. Currently, there are no pharmacological interventions that halt the progression of COPD; however one strategy is to reduce the chronic lung inflammation associated with this disease. An increased inflammatory infiltrate comprising macrophages, neutrophils and T-lymphocytes is a major hallmark of COPD. Furthermore, both macrophages and neutrophils have the ability to cause all the pathological changes associated with COPD. Chemokines that are elevated in sputum from COPD patients have the capacity to recruit neutrophils, the macrophage precursor cells, monocytes, and T-lymphocytes. Chemokines are considered predominantly chemotactic cytokines however; there is a growing body of evidence demonstrating that chemokines can also act as functional antagonists thus leading to selective recruitment of inflammatory cells. Whilst inhibition of chemokine dependent recruitment of inflammatory cells via small molecule antagonists gives rise to potential treatments for COPD, the discovery that chemokines are also natural antagonists could also be exploited in the ongoing search for treatment of this currently fatal disease.

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Apoptosis in COPD
Sandra Hodge, Greg Hodge, Mark Holmes and Paul N. Reynolds
[Full text article]

Chronic obstructive pulmonary disease (COPD) is a highly prevalent airway disease that causes serious morbidity and mortality. Despite its importance, the cellular and molecular mechanisms that contribute to COPD pathogenesis have only recently been investigated. COPD is characterised by chronic inflammation, and loss of structural integrity throughout the lung from conducting airways, to the alveolar walls. Apoptosis is an active biochemical process, associated with minimal inflammation or disruption of neighbouring tissue. Apoptosis is considered to play an important role in effective repair of an injured airway epithelium, and resolution of inflammation. However, disorders in the apoptotic process, including increased rates of epithelial cell apoptosis or defective clearance of apoptotic cells by neighbouring phagocytes, are associated with tissue injury in several conditions, including liver injury and heart disease. Increasingly, the role of apoptosis in the pathogenesis of COPD is being recognised. Several studies have reported increased apoptosis of airway epithelial cells, and defective clearance of these cells by alveolar macrophages in COPD, although how this relates to the disease process is still largely unknown. Cigarette smoking directly induces apoptosis of airway epithelial cells. However, the increased rate of apoptosis does not appear to diminish with cessation of cigarette smoking. In this regard, factors that relate to perpetuation of the chronic inflammatory response in COPD may also contribute to increased apoptosis in the airways. These include the high level of oxidative stress, release of proteolytic enzymes as a result of increased numbers of neutrophils, cytotoxic T-cells, activation of TNF-α, TGF-β and Fas pathways, and inflammatory responses to colonisation of the airways with bacteria. Understanding the role of apoptosis and phagocytosis in the airways in COPD is likely to lead to novel therapeutic approaches for this extremely common, yet, often neglected disease.

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Interleukin-1, Neutrophil Elastase, and Lipopolysaccharide: Key Pro-Inflammatory Stimuli Regulating Inflammation in Cystic Fibrosis
Tomas P. Carroll, Catherine M. Greene, Clifford C. Taggart, Noel G. McElvaney and Shane J. O’Neill
[Full text article]

Cystic fibrosis (CF) is a common fatal genetic disease among Caucasians of European descent that is characterized by neutrophil-dominated airway inflammation due to intrinsic cellular abnormalities in the affected epithelial cells. A number of proinflammatory stimuli are responsible for aggravating inflammatory responses in CF bronchial epithelium. Two important host-derived factors with potent proinflammatory effects in CF are interleukin-1 (IL-1) and neutrophil elastase (NE). Microbial-derived factors also have importance in the CF lung, as a significant factor by which pulmonary inflammation is mediated in CF is by Pseudomonas aeruginosa infection. Pseudomonas antigens, including lipopolysaccharide (LPS), can exacerbate pulmonary inflammation in CF by exaggerating proinflammatory gene expression via Toll-like receptor (TLR) activation. TLRs belong to a family of proteins that can recognize and discriminate a diverse array of microbial antigens. Following their activation TLRs transduce intracellular signals that regulate proinflammatory gene expression. Intriguingly IL-1, NE and LPS all utilize the same intracellular signaling pathways to induce their effects. This review will summarise what is known regarding the roles of these important proinflammatory stimuli and their effects on CF epithelium and describe current and novel therapeutic strategies for the treatment of CF lung disease.

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Bone Marrow-Derived Cells in the Pathogenesis of Lung Fibrosis
Bethany B. Moore, Victor J. Thannickal and Galen B. Toews
[Full text article]

Progressive pulmonary fibrosis is characterized by failed alveolar reepithelialization and fibroblast/myofibroblast accumulation, with deposition of extracellular matrix. This results in loss of lung elasticity, alveolar collapse and fibrosis, impaired gas exchange and progressive decline in pulmonary function. Myofibroblasts represent an activated, contractile cellular phenotype that are potent producers of collagen and other extracellular matrix proteins. It is generally thought that myofibroblasts derive from local tissue fibroblasts. However, recent evidence suggests a portion of the progenitors for these cells may arise from the bone marrow. Fibrocytes, which share both leukocyte and mesenchymal markers, are found in increased numbers in bone marrow and lung of injured mice. Fibrocytes circulate in blood and are recruited to injured sites via chemotactic signals. Studies with bone marrow chimeric and parabiotic mice suggest that fibroblasts (and in some cases myofibroblasts) arise from circulating bone marrow precursors. Chemokine and chemokine receptor interactions are critical for the recruitment of bone marrow-derived progenitors. Once fibrocytes arrive in injured tissues, local factors induce their differentiation into fibroblasts/myofibroblasts. This review will summarize the experimental findings, supporting a role for the participation of bone marrow-derived cells in animal models of lung fibrosis, and potential implications for the pathogenesis of fibrotic lung diseases.

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Pulmonary Surfactant-Update on Function, Molecular Biology and Clinical Implications
Joanna Floros, David S. Phelps, Ulrich Pison and Roger Spragg
[Full text article]

This review is based on the contents of an international congress entitled, “Surfactant 2004”, organized by Drs. B. Lachmann and L.M.G. van Golde and held in Berlin, Germany.

This is the fourth meeting of its kind; the first one was held in 1989. The purpose was to bring together investigators, interested in surfactant research from different disciplines to review progress in basic and clinical sciences, evaluate findings from clinical trials, and build upon the current knowledge to design better clinical trials for the prematurely born infant and other groups of patients, who are identified with surfactant dysfunction, as well as formulate new hypotheses for surfactant investigation both at the basic science and clinical science levels. Although the importance of surfactant in normal lung function was initially appreciated in the case of the prematurely born infant the importance of surfactant throughout life and the roles, especially of the surfactant proteins, not only in surfactant-related activities but also in the innate host defense of the lung has led to a tremendous increase in research activity in the field. The work presented in this meeting is summarized under four general topics: biophysical, innate host defense, surfactant proteins and pulmonary disease, and clinical studies of surfactant.

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Severe Acute Respiratory Syndrome (SARS): A Brief Review With Exploration of the Outcomes, Prognostic Factors and Sequelae
Johnny W.M. Chan and Chun Kong Ng
[Full text article]

Severe Acute Respiratory Syndromes (SARS) is a novel infectious disease with significant morbidity and mortality. While heated debates and vigorous scientific investigations are still ongoing over the treatment, prevention and infection control of this deadly disease, substantial data has been accumulated concerning the outcomes and prognostic factors. Postmortem findings of the deceased have revealed diffuse alveolar damage, together with evidence of fibrosis and organization. A number of predicting indicators such as advanced age, presence of co-morbidities, extensive radiological involvement, high coronaviral load and elevated serum lactate dehydrogenase have been identified to be independent predictors for adverse clinical outcomes such as admission to intensive care unit, mechanical ventilation, and death. A number of recovered SARS patients experienced exertional breathlessness, malaise, asthenia during the early recovery phase, while restriction and isolated reduction in diffusion capacity were the commonest lung function abnormalities identified during the subsequent follow-up visits. Radiological abnormalities including residual groundglass appearance and fibrosis were still detectable in these patients from their high-resolution computed tomography after recovery. Some recovered SARS patients were found to be suffering from psychological problems and avascular necrosis of the large joints.

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Lung Remodeling in Interstitial Pneumonia: A New Molecular Target of Pulmonary Fibrosis
Mitsuhiro Sunohara and Hajime Takizawa
[Full text article]

It is well demonstrated that inflammatory processes in the interstitium are pivotal as the pathological features of idiopathic interstitial pneumonia (IIP). Standard therapy with corticosteroids may suppress such inflammatory changes, but not result in marked clinical benefits, especially among patients with idiopathic pulmonary fibrosis (IPF). Recent studies clarified that the degrees of cell infiltration did not correlate with the clinical outcomes, but so-called remodeling processes, such as the number of fibroblastic foci, can more accurately predict the life expectancy among patients with IPF; the most common disease entity with poor prognosis. In accordance with such findings, anti-inflammatory strategies including treatment with corticosteroids, immunosuppressive agents, and even recently studied agent interferon-gamma have not been successful to stop or improve this process. More focuses should be now cast onto the molecular processes of myofibroblastic differentiation, proliferation and apoptosis of lung fibroblasts. Agents regulating these processes may become new therapeutic choices for these progressive pulmonary disorders.

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Clinical Potencies of Glucocorticoids: What do we Really Measure?
Emile F.L. Dubois
[Full text article]

Glucocorticoids (GC) are used in pulmonary medicine since the early nineteen-thirties; in the beginning by using extracts of adrenal glands of animals, later on synthetically composed and since the early nineteen-seventies in inhaled formulation. In pulmonary medicine the majority of prescriptions are related to asthma and exacerbations of COPD. In determining the pharmacological potency of the different GC’s many efforts were made for quantification. In this respect in vitro, in vivo, ex vivo and clinical studies were performed. Examples in estimating the GC potency range from skin-blanching tests to suppressive effect on the adrenal gland, the latter representing ‘a classical paradigm’. Thus far different quantifying attempts that have been made did not take into account the tissue concentration-effect relationship, which can be achieved by pharmacokinetic/pharmaco-dynamic (PK/PD) modelling. Moreover, in the clinical studies described, the suggestion was risen that GC’s may have a different potency towards each target tissue separately and that the suppressive effect on the adrenal gland does not reflect for instance its anti-inflammatory action. In this respect the studies describe a quantifying inflammation model for asthma e.g. by granulocyte colony stimulating factor (GCSF) stimulated rise in eosinophilic cationic protein (ECP), which could be inhibited by different GC’s.

In conclusion, studies on potencies of GC should comprise PK/PD modelling and should target as much as possible on the different outcome parameters of the therapeutical and adverse effects separately and simultaneously, thereby describing ‘the spectrum of potency’ of a GC rather than ‘the potency’.