| Current
Respiratory Medicine Reviews
ISSN: 1573-398X
Current Respiratory Medicine
Reviews
Volume 2, Number 3, August 2006
Contents
Editorial Pp. i-ii
Is There a Genetic Susceptibility to Bronchopulmonary
Dysplasia? Pp. 253-262
Anupama Shetty, Jeffrey R. Gruen and Vineet Bhandari
[Abstract]
A Pulmonary Perspective on GASPIDs: Granule-Associated
Serine Peptidases of Immune Defense Pp. 263-277
George H. Caughey
[Abstract]
Small Airways Disease in Asthma Pp. 279-283
Tanya Gulliver, Giovanni Piedimonte and Nemr Eid
[Abstract]
Lung Defence Mechanisms and Their Potential Role
in the Prevention of Ventilator Associated Pneumonia Pp.
285-297
Matt Wise, Josephine Lightowler and Christopher Garrard
[Abstract]
The Search for the Genetic Component of COPD: Role
of the Clinical Phenotype Pp. 299-304
Maurizio Luisetti, Isa Cerveri and Ernesto Pozzi
[Abstract]
New Developments in the Management of Pleural Effusions
Pp. 305-311
Andrew RL Medford and Nick A. Maskell
[Abstract]
Cell-Type Restricted Responses to Chronic Oxidative
Stress Pp. 313-319
Jason M. Roper and Michael A. O'Reilly
[Abstract]
An Unusual Cause of Low Oxygen Saturation in the Operating
Room Pp. 321-323
Joseph Varon, Pilar Acosta and Ross Reul
[Abstract]
Sleep-Related Disorders, Diabetes and Obesity: Understanding
the Facts Pp. 325-329
Javier Nieto, Salim Surani, Ana L. Huerta-Alardín
and Joseph Varon
[Abstract]
The Basement Membrane Zone in Asthma Pp.
331-337
Michael J. Evans, Michelle V. Fanucchi and Charles G.
Plopper
[Abstract]
The Role of Selectins During Lung Inflammation and
Their Potential Impact for Innovative Therapeutic Strategies
Pp. 339-354
Daniel Bock, Ewald M. Aydt, Wolfgang M. Kuebler and Gerhard
Wolff
[Abstract]
Abstracts
[Back to top]
Editorial
Diagnosing and Treating Pleural Effusions:
The Good, the Bad and the Ugly!
The pleural space is the coupling system between the lung
and the chest wall and it represents an important part of
the breathing apparatus [1]. Pleural infection was first described
by Hippocrates in 500 BC [2]. Pleural effusions, or abnormal
accumulations of fluid in the pleural space, can be caused
by a wide variety of intrathoracic and systemic diseases.
Fluid that enter the pleural space can originate in the interstitial
spaces of the lung, the pleural capillaries, the intrathoracic
lymphatic, or the peritoneal cavity [3]. In many instances,
the etiology of a pleural effusion is apparent from the clinical
context. For example, 40% of patients who undergo coronary
artery bypass graft develop a pleural effusion in the immediate
postoperative period [4]. Most of these effusions produce
dyspnea but not chest pain or fever, and most of them will
disappear gradually over time. In other cases, the etiology
is cumbersome and requires a high index of suspicion as well
as invasive and innovative diagnostic and therapeutic techniques
(i.e., thoracoscopy).
In this issue of Current Respiratory Medicine Reviews,
Medford and Maskell review in detail some of the advances,
myths and controversies in the management of patients with
pleural effusions [6]. Not only these authors review the current
literature, but also provide readers of the journal with evidence-based
practical points.
The treatment of pleural effusions has been a matter of debate
for decades and it primarily depends on the underlying cause(s).
For example, treatment directed at congestive heart failure
reduces the pleural fluid most of the time. Removal of the
offending drug often resolves drug-induced pleural effusion.
However, in other conditions, such as empyema and malignant
pleural effusions, the treatment options are not straight-forward.
There is great variation Worldwide in the management of patients
with pleural infection, and approaches differ between clinicians.
The very first and most popular therapeutic intervention for
empyema was surgical intervention having a high mortality
rate and serious complications. In 1875 the first closed water-seal
drainage for empyema was described by Gotthard Bulau but not
widely used [2]. A military commission in 1918 introduced
a treatment program of repeated tapping observing favorable
results. Recommendations from this commission included drainage
with closed chest tube, avoidance of early open drainage,
obliteration of the pleural space, and proper nutritional
support which remain the basis of treatment of these patients
today [7]. The publication of guidelines for the management
of pleural effusions by the British Thoracic Society (BTS)
aimed predominantly at physicians involved in general and
respiratory medicine. The BTS guidelines objective was to
have a rapid evaluation and therapeutic intervention that
would reduce morbidity and mortality, as well as health care
costs [8].
As noted by Medford and Maskell, attempting to establish the
diagnosis of a pleural infection for prompt decompressive
drainage requires a pleural pH analysis. Unfortunately, this
test has many limitations and can have spurious values. The
authors of this review article concisely describe accepted
guidelines and challenge the use of this test under certain
circumstances.
When clinicians are confronted with a patient with a malignant
pleural effusion, pleurodesis may be accomplished using a
variety of agents. Medford and Maskell note that significant
controversy still exists as to the “ideal” agent
for sclerosis of the pleural surface. Their evidence-based
suggestions may contradict other proponents of alternate sclerosing
agents.
Pleural effusions remain a common problem in medicine, and
any diagnostic algorithm should be based on knowledge of the
limitations of the studies involved. Reviews such as the one
by Medford and Maskell are important for pulmonary and chest
physicians as they provide current and up-to-date literature
support for the limitations that current available diagnostic
and therapeutic techniques may have.
REFERENCES
[1] Bartter T, Santarelli R, Akers SM, et al. The
evaluation of pleural effusion. Chest 1994; 106:1209-14.
[2] Meyer JA. Gotthard Bulau and closed water-seal drainage
for empyema, 1875-1891. Ann Thorac Surg 1989; 48:597-9.
[3] Light RW, Macgregor MI, Luchsinger PC, et al.
Pleural effusions: the diagnostic separation of transudates
and exudates. Ann Intern Med 1972; 77: 507-13.
[4] Light RW, Rogers JT, Moyers JP, et al. Prevalence
and clinical course of pleural effusions at 30 days after
coronary artery and cardiac surgery. Am J Respir Crit Care
Med 2002; 166:1567-71.
[5] Ferrer J, Roldan J, Teixidor J, et al. Predictors
of pleural malignancy in patients with pleural effusion undergoing
thoracoscopy. Chest 2005; 127:1017-22.
[6] Medford AR, Maskell NA. New developments in the management
of pleural effusions. Curr Respir Med Rev 2006; 2: 305-311.
[7] Peters RM. Empyema thoracis: Historical perspective. Ann
Thorac Surg 1989; 48:306-8.
[8] Davies CWH, Gleeson FV, Davies RJO. BTS guidelines for
the management of pleural infection. Thorax 2003; 58:18-28.
Pilar Acosta
Facultad de Medicina de Tampico
Universidad Autónoma de Tamaulipas
Tampico
Mexico
Joseph Varon
(Editor-in-Chief)
2219 Dorrington Street
Houston
Texas 77030
USA
E-mail: Joseph.Varon@uth.tmc.edu
[Back to top]
Is There a Genetic Susceptibility to Bronchopulmonary
Dysplasia?
Anupama Shetty, Jeffrey R. Gruen and Vineet Bhandari
Bronchopulmonary Dysplasia (BPD) continues to be a major problem
despite advances in the management of the sick preterm. Current
evidence supports a multifactorial etiology to this disease.
Prematurity is the cardinal factor; others include pulmonary
baro/volu trauma, hyperoxia, and inflammation.
A clearer understanding of genetic susceptibility for BPD
has recently emerged. Twin studies have shown that 53% of
the variance for BPD is genetic. This article will attempt
to review the published literature appraising the relationship
between single nucleotide polymorphisms of putative causal
genes and susceptibility to BPD. These studies, though small
in size, spark interest in further genetic association studies
to identify candidate genes that contribute to the diverse
pathophysiology of BPD.
[Back to top]
A Pulmonary Perspective on GASPIDs: Granule-Associated
Serine Peptidases of Immune Defense
George H. Caughey
Airways are protected from pathogens by forces allied with
innate and adaptive immunity. Recent investigations establish
critical defensive roles for leukocyte and mast cell serine-class
peptidases garrisoned in membrane-bound organelles-here termed
Granule-Associated Serine Peptidases of Immune Defense, or
GASPIDs. Some better characterized GASPIDs include neutrophil
elastase and cathepsin G (which defend against bacteria),
proteinase-3 (targeted by anti-neutrophil antibodies in Wegener’s
vasculitis), mast cell β-tryptase
and chymase (which promote allergic inflammation), granzymes
A and B (which launch apoptosis pathways in infected host
cells), and factor D (which activates complement’s alternative
pathway). GASPIDs can defend against pathogens but can harm
host cells in the process, and therefore become targets for
pharmaceutical inhibition. They vary widely in specificity,
yet are phylogenetically similar. Mammalian speciation supported
a remarkable flowering of these enzymes as they co-evolved
with specialized immune cells, including mast cells, basophils,
eosinophils, cytolytic T-cells, natural killer cells, neutrophils,
macrophages and dendritic cells. Many GASPIDs continue to
evolve rapidly, providing some of the most conspicuous examples
of divergent protein evolution. Consequently, students of
GASPIDs are rewarded not only with insights into their roles
in lung immune defense but also with clues to the origins
of cellular specialization in vertebrate immunity.
[Back to top]
Small Airways Disease in Asthma
Tanya Gulliver, Giovanni Piedimonte and Nemr Eid
Small airway plays a major role in viral infection of
the respiratory tract in infants and young children. Indeed
these early viral infections have been shown to lead to airway
remodeling and early development of non allergic asthma by
affecting the expression of critical growth factors. In the
old child and adult however, and until very recently, asthma
has been considered largely a disease of the large airways.
But as our understanding of asthma evolves, it now seems that
the disease process in asthma is located in all parts of the
tracheobronchial tree, small airways, and alveoli. Small airway
remodeling has the potential to produce fixed airflow obstruction,
which if untreated and unrecognized can lead chronic obstructive
pulmonary disease.
With the recognition of the important role of the small airways
in the pathogenesis of asthma in infants as well as in adults,
more aggressive modalities of treatment are urgently needed
in order to have a positive impact on asthma outcome. This
article will review the impact of early viral infections on
airway remodeling in infants, the role that small airways
play in older asthmatics, and finally the potential role of
new HFA formulation for the treatment of asthma.
[Back to top]
Lung Defence Mechanisms and Their Potential Role
in the Prevention of Ventilator Associated Pneumonia
Matt Wise, Josephine Lightowler and Christopher Garrard
Ventilator associated pneumonia remains a cause of significant
morbidity and mortality in Intensive Care patients despite
advances in knowledge and technology. The presence of an endotracheal
tube bypassing the normal airway barriers, oropharyngeal bacterial
colonisation, patient position and repetitive micro-aspiration
tip the host-pathogen relationship in favour of the pathogen
and promote lung infection in a time-dependent manner. Defending
the lung against microbial invasion and infection is a multiplicity
of innate and adaptive immune mechanisms, which can identify
and eliminate potential pathogens. These defence mechanisms
include the ability to recognise pathogens through cell-surface
receptors, antimicrobial peptides and proteins, pro and anti-inflammatory
mediators and factors related to the coagulant state of the
lung fluid. The mechanisms are characterised by their complexity,
their remarkable degree of redundancy and effectiveness.
[Back to top]
The Search for the Genetic Component of COPD: Role
of the Clinical Phenotype
Maurizio Luisetti, Isa Cerveri and Ernesto Pozzi
Chronic obstructive pulmonary disease (COPD) is a common,
complex disorder, and dissection of its individual components
is considered one of the research priorities for this disease.
Several lines of evidence suggest that, in spite of the massive
role of cigarette smoking, common COPD is not just an environmental
phenocopy of COPD associated with alpha1-antitrypsin
deficiency: from the racial/ethnic variability in COPD prevalence
to the individual susceptibility to cigarette smoke, from
the familial aggregation of lung function levels to the familial
clustering of COPD symptoms, all lines tend to point to common
COPD having a genetic component. The challenge in the last
three decades has been to define the borders of this component,
its relative weight with respect to the environmental component,
and to identify the susceptibility and/or resistance genes.
Taking advantage from the knowledge, albeit limited, of the
biochemical basis of COPD, a number of genetic polymorphisms
have been investigated, mostly in case-control association
studies. Although such a strategy is considered more successful
than linkage analysis for investigating complex, non-Mendelian
disorders and in spite of the considerable amount of data
collected, the overall result of the genetic investigations
into COPD has so far been largely disappointing. A critical
evaluation of the published reports shows that a number of
issues could have affected the outcome of the investigations:
among such issues, the choice of the appropriate clinical
phenotype is fundamental.
[Back to top]
New Developments in the Management of Pleural Effusions
Andrew RL Medford and Nick A. Maskell
Pleural diseases are a commonly encountered problem by general
physicians and chest specialists alike. Despite this, there
has been a lack of research over the last few decades in this
important field. This review focuses on new developments in
the management of pleural effusions. We have restricted our
attention, in the main, to randomised controlled trials. The
review is evidence-based with practical suggestions from the
authors to practicing clinicians. Specific areas focused on
are pleural infection and malignant pleural disease.
In pleural infection, the importance of pleural pH is emphasised
and we have incorporated the latest evidence on the use of
fibrinolytics from the recent multi-centre randomised controlled
MIST trial.
In malignant pleural effusion, the best way of obtaining closed
pleural biopsy is discussed. With regard to pleurodesis, recent
data on the importance of knowing your talc particle size
is highlighted, as well as the role of fibrinolytics, thoracoscopy
and when to use Pleurx catheters. Finally, the latest developments
on newer diagnostic markers such as mesothelin in mesothelioma
and newer anti-pleural agents such as transforming growth
factor-beta (TGF-β)
and vascular endothelial growth factor (VEGF) antagonists
have been reviewed.
[Back to top]
Cell-Type Restricted Responses to Chronic Oxidative
Stress
Jason M. Roper and Michael A. O'Reilly
Exposure to hyperoxia (> 95% O2)
is a necessary therapeutic treatment used to maintain tissue
oxygenation in patients with compromised lung function and
decreased pulmonary gas exchange. Hyperoxia causes increased
formation of reactive oxygen species (ROS), which accumulate
in the cells of the lung resulting in cell death and compromised
tissue function. Recent observations have demonstrated that
different lung cell types respond differently to increased
oxidative stress raising many questions about the cell-type
restricted response of different pulmonary cell types. This
review will focus on three main aspects of chronic oxidative
stress in a cell-type specific manner: the role of antioxidant
defenses, DNA repair, and apoptotic signaling.
[Back to top]
An Unusual Cause of Low Oxygen Saturation in the Operating
Room
Joseph Varon, Pilar Acosta and Ross Reul
Pulse oximetry is commonly used in clinical practice as an
indirect monitor of blood oxygen saturation. There are many
factors, however, that can interfere with accurate readings.
We present a case of a woman with metastatic thyroid cancer
that had a sudden drop in her pulse oximetry during bronchoscopy
and that eventually was found to have an uncommon cause for
a misleading persistently low oxygen saturation.
[Back to top]
Sleep-Related Disorders, Diabetes and Obesity: Understanding
the Facts
Javier Nieto, Salim Surani, Ana L. Huerta-Alardín
and Joseph Varon
For decades, neurologic and pulmonary disorders have been
associated to diabetes mellitus (DM) and more recently to
obesity. Many studies have attempted to establish the association
between sleep apnea and adult-onset DM. Growing evidence exists
demonstrating the association between insulin-resistance and
obstructive sleep apnea (OSA), as well as sleep-disordered
breathing (SDB) in non-obese diabetic patients with autonomic
neuropathy. In patients with DM, two types of sleep disorders
can be found; upper airway resistance syndrome and sleep apnea.
The later apnea can be central, obstructive or mixed. In either
case, a decrease in the oxygen saturation will ensue, and
sleep arousal will occur. The diagnosis of sleep apnea in
patients with DM is mainly done by obtaining a good history
and physical examination. The main symptoms in the patient
with sleep apnea include excessive daytime sleepiness (frequently
seen in situations which are not mentally demanding). Effective
continued positive airway pressure (CPAP) treatment show clinical
improvement in symptoms as well as in insulin sensitivity.
The relation between SDB and DM can have significant impact
on the over-all health of the patient.
[Back to top]
The Basement Membrane Zone in Asthma
Michael J. Evans, Michelle V. Fanucchi and Charles G.
Plopper
Thickening of the basement membrane zone (BMZ) is a characteristic
feature of airway remodeling. The BMZ appears as three component
layers: the laminas lucida, densa, and reticularis. The lamina
reticularis of the BMZ is thickened in asthma, allergic rhinitis,
eosinophil bronchitis and lung transplants. Collagen types
I, III and V form heterogeneous fibers that account for the
thickness of the BMZ. Proteoglycans are structural component
of the BMZ responsible for many of its functions, in particular,
trafficking of growth factors and cytokines between epithelial
and mesenchymal cells. An important function of the BMZ is
storage and regulation of fibroblast growth factor-2 (FGF-2).
FGF-2 has been shown to be involved with normal growth and
thickening of the BMZ. Treatment with corticosteroids reduces
the width of the BMZ in asthmatics. The significance of BMZ
thickening in airway function is not clear however, it may
have a positive effect by physically protecting against airway
narrowing and air trapping. Thickening of the BMZ may have
a negative effect by influencing how the epithelial mesenchymal
trophic unit functions. However at this point there are no
studies showing abnormal trafficking of growth factors and
cytokines due to thickening of the BMZ.
[Back to top]
The Role of Selectins During Lung Inflammation and
Their Potential Impact for Innovative Therapeutic Strategies
Daniel Bock, Ewald M. Aydt, Wolfgang M. Kuebler and Gerhard
Wolff
The selectin family of cell adhesion molecules (selectins)
is comprised of three structurally related calcium-dependent
carbohydrate binding proteins, E-, P-, and L-selectin. Located
on the surface of endothelial cells (E- and P-selectin), platelets
(P-selectin) and of leucocytes (L-selectin), selectins are
of vital importance for leukocyte recruitment and accumulation
in the vasculature. Based on the unique architecture of the
microvasculature of the lung, this task is achieved by two
different types of selectin mediated functions (i) tethering
and rolling of leukocytes on the pre- and post capillary pulmonary
endothelium and in bronchial venules which are mediated by
E-, P-, and L-selectin as well as (ii) retention of leukocytes
in the pulmonary capillaries by L-selectin. Recent findings
in preclinical and clinical research suggest a significant
involvement of selectins in both acute and chronic inflammatory
lung diseases such as acute lung injury (ALI), acute respiratory
distress syndrome (ARDS), asthma bronchiale (Asthma), chronic
obstructive pulmonary disease (COPD) or idiopathic pulmonary
fibrosis (IPF). This review summarizes the current progress
in understanding the role of selectins during inflammation
in the lung and its potential impact for innovative therapeutic
strategies.
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