| Current
Respiratory Medicine Reviews
ISSN: 1573-398X
Current Respiratory Medicine
Reviews
Volume 1, Number 3, November 2005
Contents
The Behavioral Control of Breathing: Sensory and Motor Aspects
Pp.219
Murray D. Altose and Neil S. Cherniack
[Abstract]
Risk Stratification in Pulmonary Embolism Pp.227
Mark Weatherhead and George Antunes
[Abstract]
Tumor Necrosis Factor-α-Mediated
Pulmonary Endothelial Barrier Dysfunction Pp.233
Daniel J. Angelini, Jeffrey D. Hasday, Simeon E. Goldblum
and
Douglas D. Bannerman
[Abstract]
The Physiological Basis of Respiratory Sensation Pp.247
Melody Yu and Yves Jammes
[Abstract]
Tuberculosis Deaths Among Populations with High HIV
Prevalence Pp.253
Dermot Maher
[Abstract]
Severe Hemorrhagic Cystitis Associated with BK Polyoma
Virus Infection Following Lung Transplantation Pp.261
Lingtak-Neander Chan, Malek G. Massad, Kamran Mahmood,
Nina Clark, Sally Steinhiser, Jacques Kpodonu, Cimenga Tshibaka
and Howard A. Jaffe
[Abstract]
Severe Community-Acquired Pneumonia (CAP) due to Atypical
Pathogens Pp.265
Argyris Michalopoulos, Michael Rizos and Matthew E. Falagas
[Abstract]
C/EBP Transcription Factors in Lung Disease Pp.273
Magnus Nord
[Abstract]
Acute Inflammatory Gastric Aspiration-Related Lung
Injury Pp.279
Krishnan Raghavendran, Bruce A. Davidson, Patricia R.
Chess,
Nader D. Nader, Robert H. Notter and Paul R. Knight
[Abstract]
Milestones in the Development of Chronic LPS-Induced
Airway Disease Pp.291
David M. Brass and Jordan D. Savov
[Abstract]
Genetics of Chronic Obstructive Pulmonary Disease
Pp.297
Ahmed E. Hegab, Tohru Sakamoto and Kiyohisa Sekizawa
[Abstract]
HIV and Respiratory Disease: A Contemporary Perspective
Pp.307
Albert E. Holt IV, Wendy Turenne and Anthony D. Slonim
[Abstract]
Radiation-Induced Lung Injury Following Therapy for
Thoracic Malignancy Pp.317
Ross K. Morgan, Lisa A. Kachnic and Ross Summer
[Abstract]
Transforming Growth Factor-β Peptide Signaling
in Lung Development: Bronchopulmonary Dysplasia, Lung Fibrosis
and Emphysema Pp.325
David Warburton, Wei Shi, Martin Kolb and Jack Gauldie
[Abstract]
Abstracts
[Back to top]
The Behavioral Control of Breathing: Sensory and
Motor Aspects
Murray D. Altose and Neil S. Cherniack
Breathing movements are directed both reflexly by neurons
in the medulla and pons and behaviorally through cortical
and limbic neurons. The two modes of control have afferent
and efferent interconnections and interact continuously but
their relative influences shift considerably through the sleep-waking
cycle. In an awaked state behavioral control prevents apnea
and by itself is able to maintain normal blood gas tensions
except during exercise above the anerobic threshold. During
sleep the maintenance of breathing depends on input from chemoreceptors.
If apnea should occur during sleep, this is regularly followed
by arousal so as to return the control of breathing to the
behavioral system. In certain pathological states breathing
is persistently regulated either automatically as in the “locked
in” syndrome or voluntarily in the congenital central
hypoventilation syndrome.
Respiratory movements and forces produce sensations that
can be accurately perceived and when sufficiently intense
result in symptoms of shortness of breath or dyspnea. This
in turn can initiate volitional adjustments in the level and
pattern of breathing. Dyspnea can have both beneficial and
adverse effects. In asthmatics, dyspnea serves as an early
warning signal of airway narrowing; but in patients with chronic
airways obstruction or in patients with normal lungs and panic
disorder dyspnea may be an incapacitating symptom.
Recent investigations using techniques such as functional
brain imaging and electrical and magnetic brain stimulation
as well as increasingly sophisticated psychophysical approaches
have provided important insights into the workings of the
suprapontine regulation of breathing and its role in health
and disease.
[Back to top]
Risk Stratification in Pulmonary Embolism
Mark Weatherhead and George Antunes
Pulmonary embolism is a common medical problem and although
many patients have a benign clinical course there is still
appreciable morbidity and mortality associated with the diagnosis.
It is generally accepted that thrombolysis is the treatment
of choice in patients with haemodynamic compromise but the
management of haemodynamically stable patients with large
pulmonary embolism is less well defined.
A significant proportion of this latter group have a complicated
hospital course and require escalation of therapy.
There is increasing interest in markers that can potentially
identify at risk patients who would benefit from intensive
monitoring and therapy. Conversely these markers would also
identify low risk patients who could be managed on an outpatient
basis alone.
This article reviews the current evidence for the use of
the clinical history and examination, electrocardiogram, echocardiography,
computed tomography and cardiac biochemical markers, principally
troponin and brain natriuretic peptide, for risk stratification
in pulmonary embolism.
[Back to top]
Tumor Necrosis Factor-α-Mediated
Pulmonary Endothelial Barrier Dysfunction
Daniel J. Angelini, Jeffrey D. Hasday, Simeon E. Goldblum
and Douglas D. Bannerman
The multifunctional cytokine, tumor necrosis factor-alpha
(TNF-α),
is released from host cells in response to diverse injurious
stimuli and is elevated during acute lung injury. Increased
levels of TNF-α
are found in both the bloodstream and bronchoalveolar lavage
fluid of experimental and clinical settings of acute lung
injury. TNF-α
administration to experimental animals increases pulmonary
leukostasis, microvascular permeability and edema formation.
Further, TNF-α
can directly open the pulmonary vascular endothelial paracellular
pathway in vitro. TNF-α
opens the pulmonary endothelial paracellular pathway in both
a dose- and time-dependent manner independent of endothelial
cell injury/apoptosis. A prolonged stimulus-to-response lag
time between the TNF-α
stimulus and altered barrier function exists (≥2h) and
this delayed response cannot be ascribed to a requirement
for de novo protein synthesis. TNF-α
activates one or more protein tyrosine kinase(s), increases
tyrosine phosphorylation of adherens junction proteins, and
induces actin disassembly temporally coincident with opening
of the paracellular pathway; the increased protein tyrosine
phosphorylation and actin reorganization are both prerequisites
to TNF-α-induced
loss of endothelial barrier function. Febrile range hyperthermia
further enhances TNF-α
levels and its biological effects. All of these data implicate
TNF-α
in the pathogenesis of acute lung injury. Understanding the
mechanisms through which TNF-α
regulates the pulmonary microvascular paracellular pathway
should provide targets for future clinical interventions.
[Back to top]
The Physiological Basis of Respiratory Sensation
Melody Yu and Yves Jammes
Respiratory sensation often occurs in patients suffering
from acute or chronic respiratory and/or cardiac diseases,
leading to dyspnoea. It is supported by the cortical integration
of sensory pathways arising from the airways and lungs, respiratory
muscles, and circulatory system. Their activation by direct
electrical stimulation or circumstances mimicking pathological
events (mechanical and less often chemical test agents) evokes
cortical potentials and modifies the spontaneous EEG rhythms
in cortical areas which also receive information from the
skin, joints, and limb muscles. The quantification of respiratory
sensation is obtained by psychophysical methods based on different
theories linking the stimulus to its perception. Pathological
or environmental circumstances act as triggers of the dyspnoea
sensation. Ventilatory loading, elicited by dense gas breathing
and mostly pathological airway obstruction, leads to an enhanced
intrathoracic pressure and respiratory muscle work which in
turn activate the vagal and respiratory muscle afferents.
Experiments in healthy subjects testify for marked alterations
of the tactile sensation and voluntary motor control to limb
muscles when the respiratory system is loaded. These viscero-somatic
interactions could partly support the well-known phenomenon
of altered exercise performances and perception of the body
image in patients suffering from chronic respiratory diseases,
apart from any disturbances in respiratory gases.
[Back to top]
Tuberculosis Deaths Among Populations with High HIV
Prevalence
Dermot Maher
Death is the outcome of tuberculosis most feared by patients
and their families. The development of anti-tuberculosis chemotherapy
in the 1950s led to dramatic reductions in tuberculosis deaths
in populations with access to treatment. The emergence of
HIV in the 1980s reinstated tuberculosis as "a captain
of the men of death" in countries with high HIV prevalence.
The annual global toll of deaths among tuberculosis patients
is currently about 2 million. Along with reducing morbidity
and disease transmission, reducing tuberculosis deaths is
one of the objectives of tuberculosis control. The world faces
the challenge of reducing tuberculosis deaths by half by 2015,
as part of achieving the United Nations Millennium Development
Goals.
Since HIV increases the risk of death during and after tuberculosis
treatment, and is related to the degree of immunosuppression,
the total number of deaths among tuberculosis patients is
increased in populations with high HIV prevalence. Sub-Saharan
Africa is the region most badly affected by the HIV epidemic
and therefore also with the highest proportion of tuberculosis
deaths attributable to HIV. Improvements in the routine reporting
of deaths by national tuberculosis programmes will increase
the utility of tuberculosis deaths as an indicator of programme
performance. Improved epidemiological surveillance of tuberculosis
mortality depends on investment in developing vital registration
systems. Decreasing deaths among tuberculosis patients in
countries with high HIV prevalence depends on measures to
decrease tuberculosis incidence (by implementing the World
Health Organization expanded strategy to control HIV-related
tuberculosis) and to decrease tuberculosis case fatality (e.g.
health service improvements to decrease diagnostic delay,
antiretroviral treatment, co-trimoxazole).
[Back to top]
Severe Hemorrhagic Cystitis Associated with BK Polyoma
Virus Infection Following Lung Transplantation
Lingtak-Neander Chan, Malek G. Massad, Kamran Mahmood,
Nina Clark, Sally Steinhiser, Jacques Kpodonu, Cimenga Tshibaka
and Howard A. Jaffe
BK polyoma virus-associated hemorrhagic cystitis has been
described in patients who have had renal, bone marrow and
cardiac transplantation. We report the first case of hemorrhagic
cystitis associated with the BK virus in a 51 year old woman
with scleroderma, who received bilateral lung transplantation.
The pathological findings of the bladder were large cells
with enlarged nuclei and scant cytoplasm (Decoy cells). The
diagnosis was confirmed by immunohistochemical stains of the
urinary bladder tissue and by blood and urine PCR. The patient
required a cystectomy.
[Back to top]
Severe Community-Acquired Pneumonia (CAP) due to Atypical
Pathogens
Argyris Michalopoulos, Michael Rizos and Matthew E. Falagas
Community-acquired pneumonia (CAP) is a relatively common
and potentially serious infection that affects both immunocompetent
and immunosuppressive adults throughout the world. The annual
incidence of CAP in the United States is approximately 4 million
cases. CAP due to atypical pathogens accounts for approximately
20 to 40 percent of cases necessitating hospitalization. There
are few data regards to the prevalence rates of severe CAP
due to atypical pathogens necessitating admission to the intensive
care unit. This review article summarizes clinical features,
diagnostic criteria, differential diagnosis, and management
based on guidelines of medical societies.
[Back to top]
C/EBP Transcription Factors in Lung Disease
Magnus Nord
CCAAT/enhancer binding proteins (C/EBPs) are key-regulators
of cell differentiation and linked processes such as proliferation,
apoptosis and gene expression in several organs. C/EBPs are
also central for inflammatory responses and infectious defenses,
but so far little is known of their role in lung diseases.
However, a role for these intracellular proteins has recently
been suggested in asthma, lung cancer and chronic bronchitis-COPD.
In this mini-review, an overview of the biological roles of
C/EBPs in lung is provided, together with a discussion of
the recent studies suggesting a role for these transcription
factors in the pathogenesis of some of our most common and
severe lung diseases.
[Back to top]
Acute Inflammatory Gastric Aspiration-Related Lung
Injury
Krishnan Raghavendran, Bruce A. Davidson, Patricia R.
Chess, Nader D. Nader, Robert H. Notter and Paul R. Knight
This article reviews research on acute inflammatory lung
injury induced by gastric aspiration in animal models. The
innate pulmonary inflammatory response and the severity of
lung injury depend strongly on the nature of the gastric aspirate:
hydrochloric acid (ACID, pH 1.25), small non-acidified gastric
particles (SNAP), or combined acid and small gastric particles
(CASP). The "two-hit" pathology of CASP aspiration
in rodents is directly relevant for clinical gastric aspiration,
and may lead to an increased risk for progression to clinical
acute lung injury (ALI) or the acute respiratory distress
syndrome (ARDS). Rodents (rats, mice) with CASP aspiration
have more severe acute pulmonary injury based on decreased
PaO2/FiO2 ratios and increased albumin
levels in bronchoalveolar lavage (BAL) compared to rodents
given ACID or SNAP alone. Rodents given CASP also have increased
inflammation based on levels of cytokines and chemokines in
BAL during the 48 hr period post-aspiration. Recent research
has used hierarchical cluster analysis and statistical modeling
to define more specific correlations between lavaged inflammatory
mediators and lung injury severity in rodents with ACID, SNAP,
and CASP aspiration. Studies in transgenic murine models (e.g.,
MCP-1 (-/-) mice) have also been done to help assess the functional
importance of particular mediators in aspiration injury. In
addition to reviewing the effects of "two-hit" aspirates
like CASP, this article also describes research on combination
injuries where a second injury inducer (hyperoxia, lung contusion
from blunt chest trauma, or instilled E. coli bacteria)
is present concurrently with gastric aspiration. The concept
of multi-hit injury to the lungs has major clinical significance.
A single insult such as acid aspiration may be relatively
well tolerated by the pulmonary parenchyma, but the presence
of a concurrent or subsequent second insult such as particulate
aspiration, hyperoxia, or pulmonary bacterial infection may
lead to profound respiratory dysfunction with physiological
attributes of ALI/ARDS.
[Back to top]
Milestones in the Development of Chronic LPS-Induced
Airway Disease
David M. Brass and Jordan D. Savov
Lipopolysaccharide (LPS) inhalation challenge is emerging
as an experimental system for modeling environmental airway
disease such as that seen in agricultural workers, and it
can also serve as a model of environmental asthma. Mice exposed
chronically to LPS develop all of the classical features of
asthma including reversible airflow obstruction and inflammation,
persistent airway hyperreactivity (AHR), and airway remodeling.
Thickening and fibrosis of the subepithelial region of the
airway wall is a consistent histologic feature of both environmental
airway disease and of asthma that is directly related to the
clinical severity of the disease. Lessons learned from such
model systems may help to identify mechanisms that are fundamental
to the development of chronic environmental airway disease
and asthma.
[Back to top]
Genetics of Chronic Obstructive Pulmonary Disease
Ahmed E. Hegab, Tohru Sakamoto and Kiyohisa Sekizawa
Cigarette smoking is the main risk factor for chronic obstructive
pulmonary disease (COPD). However, not all smokers develop
clinically significant symptoms. It is recognized that multiple
genetic factors and genotype-by-environment interactions are
involved in the development of COPD. Remarkable progress in
the genetic knowledge and technology has changed the approaches
used to identify candidate genes. Genome-wide linkage analyses
have revealed several chromosomal regions linked to COPD phenotypes.
The recently introduced gene expression profiling techniques
have identified hundreds of genes differentially expressed
in COPD. Case-control association studies have reported more
than 30 polymorphisms related to the susceptibility to COPD.
However, the replication of these results has been limited.
In this review, we present our current understanding of the
genetic basis of COPD and the findings of genetic studies.
The advantages and limitations of the different genetic approaches
are also discussed. The increasing knowledge of the COPD genetics
combined with a better understanding of its clinical and pathological
heterogeneity will have a great potential to change views
on the pathogenesis and diagnosis, and even to influence the
clinical management.
[Back to top]
HIV and Respiratory Disease: A Contemporary Perspective
Albert E. Holt IV, Wendy Turenne and Anthony D. Slonim
Human immunodeficiency virus (HIV) infection first manifested
itself as Acquired Immune Deficiency Syndrome (AIDS) in the
early 1980s when young, previously healthy homosexual men
presented with Pneumocystis carinii pneumonia (PCP).
Since the discovery of HIV and AIDS, many different respiratory
infections (common, uncommon and opportunistic), as well as
different malignancies such as Kaposi’s sarcoma, and
destructive lung processes, such as emphysema have been shown
to occur more commonly in the setting of HIV. Alterations
in the CD4+/CD8+ lymphocyte composition and changes in the
function of B cells compromise host defenses and predispose
an HIV infected individual to respiratory infections. Highly
Active Antiretroviral Therapy (HAART) has dramatically altered
the course of HIV infection through suppression of viral replication,
a reconstitution of CD4+ cells, and the resultant decrease
in opportunistic infections, including PCP. This manuscript
provides a contemporary review of the respiratory diseases
of patients with HIV.
[Back to top]
Radiation-Induced Lung Injury Following Therapy for
Thoracic Malignancy
Ross K. Morgan, Lisa A. Kachnic and Ross Summer
Radiation therapy is a widely used treatment for locally
advanced non-small cell lung cancer, as well as for a variety
of other thoracic malignancies. Radiation induced lung injury
(RILI) refers to any lung-related change resulting from this
treatment. From a clinical standpoint, RILI is separated into
two distinct syndromes: an acute pneumonitis beginning 2-10
weeks following RT and a more indolent fibrotic process, presenting
months after initial exposure. A variety of factors have been
identified that are associated with an increased risk of developing
clinically significant RILI. These include treatment-related
factors (dose and schedule of radiation, volume of lung irradiated,
concurrent use of chemotherapy) and patient-related factors
(age, gender, smoking status, presence of pre-existing lung
disease). New insights into the mechanisms of radiation induced
lung injury have been uncovered, and these findings have led
to the development of novel strategies for the prevention
and treatment of this complication. In this review, we will
discuss the clinical manifestations and risk factors of RILI,
and focus on recent advances in its pathogenesis and treatment.
[Back to top]
Transforming Growth Factor-β;
Peptide Signaling in Lung Development: Bronchopulmonary Dysplasia,
Lung Fibrosis and Emphysema
David Warburton, Wei Shi, Martin Kolb and Jack Gauldie
Recent findings show that the TGFβ
peptide superfamily signaling pathway is not only essential
for both prenatal and postnatal lung morphogenesis, but also
plays a key role in the pathobiology of bronchopulmonary dysplasia,
lung fibrosis and emphysema. Exquisitely tight regulation
of TGFβ
bioavailabilty and function is mediated at all levels of signal
transduction from the extracelluar space to the nucleus. While
the potential for therapeutic manipulation of TGFβ
function is great, the practical application to pulmonary
medicine will be exigent because of the requirement for exact
modulation of TGFβ
bioactivity and signaling within a very narrow physiological
range.
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