| Current
Respiratory Medicine Reviews
ISSN: 1573-398X
Current Respiratory Medicine
Reviews
Volume 3, Number 2, May 2007
Contents
Editorial Pp. 93
Cell Therapy for Respiratory Diseases: Optimizing
Cell Delivery Strategies Pp. 95-99
Golnaz Karoubi, David W. Courtman and Ray C.J. Chiu
[Abstract]
New Agents for the Treatment of Tuberculosis on Clinical
Study Phases II/III Pp. 101-106
Marcus B. Conde and Margarita Elsa Villarino
[Abstract]
Clinical and Prognostic Implications of Cognitive
Dysfunction and Depression in COPD Pp. 107-115
Andrea Corsonello, Claudio Pedone and Raffaele Antonelli
Incalzi
[Abstract]
The Nature of Immunological Reaction in the Peripheral
Airways of Cigarette Smokers Pp. 117-127
Joanna Domagala-Kulawik
[Abstract]
Current Treatment of the Pulmonary Arterial Hypertension
Pp. 129-134
Juan C. Gallego-Page
[Abstract]
Prediction and Prevention of Abnormal Antenatal Lung
Growth Pp. 135-140
Michael Prendergast and Anne Greenough
[Abstract]
The Role of Corticosteroids in Sepsis and Acute Respiratory
Distress Syndrome Pp. 141-146
MeiLan K. Han and Robert C. Hyzy
[Abstract]
New Insights into the Biology of α1-Antitrypsin
and its Role in Chronic Obstructive Pulmonary Diseases
Pp. 147-158
Sabina M. Janciauskiene, Tim Stevens and Ignacio Blanco
[Abstract]
Role of Tyrosine Kinase Inhibitor Molecules in Non
Small Cell Lung Cancer: From Benchside to Bedside
Pp. 159-167
Alessia Catassi, Alfredo Cesario, Pierluigi Granone and
Patrizia Russo
[Abstract]
Abstracts
[Back to top]
Editorial
In their original description Ashbaugh and coworkers,
in 1967, described a syndrome characterized by refractory
hypoxemia, diffuse lung infiltrates on chest radiograph, and
decreased lung compliance in a group of 12 patients suffering
from severe respiratory failure [1]. This syndrome would be
later known as the adult or acute respiratory distress syndrome
(ARDS). The mainstay therapy of ARDS for the past 5 dec-ades
has remained the management of the underlying disorder causing
it, when feasible. To date, there are no specific pharmacological
interventions of proven value for the treatment of ARDS. Although
corticosteroids and other agents have been widely used clinically,
large multi-center trials in the past have failed to show
any benefit in outcome, lung compliance, pulmonary shunts,
chest radiograph, severity score or survival [2-4]. For years,
the role of corticosteroids in ARDS has been controversial
at best. These agents may have, however, a role in situations
when ARDS has been precipitated by a corticosteroid-responsive
process, such as acute eosinophilic pneumonia.
Sepsis is by far the most common cause ARDS [5,6]. The mortality
rate for patients with sepsis complicated by ARDS has been
reported to be as high as 60% [5,6]. In this clinical entity,
the role of corticosteroids has been redefined in recent years.
In this issue of Current Respiratory Medicine Reviews, Han
and Hizy extensively review the role of corticosteroids in
the critically ill patient with sepsis and ARDS [7]. These
authors review the importance of the hypothalamic-pituitaryadrenal
(HPA) axis in critical illness.
Over the past two decades, evidence-based medicine has found
that the activation of the HPA axis with the production of
adrenocorticotrophin (ACTH) and cortisol is a fundamental
part of the host response to stress such as ARDS or sepsis.
Glucocorticoids in this context, appear to have two vital
and disparate effects that allow the host to deal with acute
stress. One is the permissive effect of steroids to prepare
the host for a “fight and flight” response by
providing a ready source of fuel (glucose) and adequate hemodynamic
reserve. The second function is to suppress activated defense
mechanisms, preventing them from overshooting and damaging
the host.
The HPA axis and the immune response are linked in a negative
feedback loop, in which activated immune cells produce cytokines
that signal increased immune activity to the brain, thereby
stimulating the HPA axis, which through glucocorticoids suppress
the immune reaction [8]. Cytokines, which are produced both
in patients with sepsis and ARDS, however, also suppress the
HPA-axis and glucocorticoid receptor function. For example,
tumor necrosis factor (TNF) - alpha impairs ACTH release,
and a number of clinical studies have reported inappropriately
low ACTH levels in patients with severe sepsis and the systemic
inflammatory response syndrome (SIRS) [9-10].
As noted by Han and Hizy, acute adrenal insufficiency should
always be suspected in critically ill patients who fail to
respond to catecholamines. An ACTH infusion test and a trial
of stress doses of glucocorticoids pending the results is
suggested when this disorder is suspected.
Whether or not corticosteroids will be used routinely in patients
with sepsis complicated with ARDS in the absence of adrenal
dysfunction is a matter of constant debate and likely to continue
for years to come.
REFERENCES
[1] Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory
distress in adults. Lancet 1967; 2: 319 323.
[2] Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray
JF. Ineffectiveness of high dose methylprednisolone in preventing
parenchymal lung injury and improving mortality in patients
with septic shock. Am Rev Respir Dis 1988; 138: 62 68.
[3] Bernard GR, Luce J, Sprung C, et al. High-dose
corticosteroids in patients with the adult respiratory distress
syndrome. N Engl J Med 1987; 317: 1565 1570.
[4] Melot C, Leujeune P, Leemam M, Moraine JJ, Neaije R. Prostaglandin
E1 in the adult respiratory distress syndrome. Am Rev Respir
Dis 1989; 139: 106 110.
[5] Marik P, Varon J. Sepsis: State-of-the-art. Dis Month
2001; 42: 462-532.
[6] Lechin AE, Varon J. Adult respiratory distress syndrome
(ARDS): The basics. J Emerg Med, 1994; 12(1): 63-8.
[7] Han MK, Hyzy RC: The role of corticosteroids in sepsis
and acute respiratory distress syndrome. Curr Respir Med Rev
2007; 3: 141-146.
[8] Zaloga GP, Bhatt B, Marik PE. Critical illness and systemic
inflammation. In: Practice and Principles of endocrinology
and Metabolism, edited by Becker K, Nylen E. Philadelphia:
Lippincott Williams & Wilkins, 2001: 2068-2076.
[9] Jurney TH, Cockrell JL, Lindberg JS, Lamiell JM, Wade
WE. Spectrum of serum cortisol response to ACTH in ICU patients.
Correlation with degree of illness and mortality. Chest 1987;
92: 292 295.
[10] Schein RMH, Sprung CL, Marcial E. Plasma cortisol levels
in patients with septic shock. Crit Care Med 1990; 18: 259
263.
Joseph Varon
(Editor-in-Chief)
2219 Dorrington Street
Houston
Texas 77030
USA
E-mail: Joseph.Varon@uth.tmc.edu
Pilar Acosta
Dorrington Medical Associates, PA
Houston
Texas 77030
USA
[Back to top]
Cell Therapy for Respiratory Diseases: Optimizing
Cell Delivery Strategies
Golnaz Karoubi, David W. Courtman and Ray C.J. Chiu
Cell therapy is a new research approach being vigorously pursued
for the treatment of patients who suffer from many respiratory
diseases, ranging from acute respiratory distress syndrome
(ARDS), emphysema to idiopathic pulmonary hypertension etc.
In such studies, stem cells or progenitor cells are administered
with the goal to regenerate damaged pulmonary tissues and
to improve their functions. Various adult and embryo derived
stem cells are being employed for such investigations. However,
as the first crucial step for this approach to be successful,
cell delivery methods need to be optimized such that the cells
can not only reach the target organs but also can be retained
in sufficient quantities.
The optimal strategy for cell delivery will depend on the
anatomical and functional characteristics of the target organs.
For example, for solid organs such as the brain (e.g. for
Parkinson's disease) or the heart (for myocardial infarction),
direct injection of the cells is being employed, although
for the latter, powerful myocardial contractions could cause
massive mechanical cell loss from the cell implant sites.
For the islet cell transplants (for diabetes), intrahepatic
implantation via portal vein appears convenient and
effective. As the lung is neither a solid nor an endocrine
organ, cell delivery via vascular route appears mandatory.
It is now well established that many marrow derived stem /
progenitor cells, such as the endothelial progenitor cells
(EPCs), are capable of homing in to the tissues suffering
from acute injuries (e.g. the lung with ARDS). The roles of
inflammatory cytokines and endothelial adhesion molecules
for such homing mechanism are being elucidated. Thus for patients
suffering from acute lung injuries, intravenous administration
of donor cells could be an effective method of cell delivery.
However, in patients with chronic conditions such as emphysema,
pulmonary fibrosis or hypertension, intravascular delivery
of cells results in minimal cell retention, as the donor cells
will pass through the pulmonary circulation readily.
In this review, we will examine a number of respiratory diseases
for which stem cell therapy is being studied, then focusing
on the strategies to enable the "trapping" of donor
cells administered into the pulmonary circulation in lungs
without acute injuries. They may include the pre-treatment
of the pulmonary capillary endothelium to induce the expression
of adhesion molecules, and more recently the use of innovatively
engineered biodegradable microcapsules which can enhance intravascular
cell retention and survival. Successful strategies to deliver
donor cells to the lung will enable us to rigorously examine
the efficacy of cell therapy, thus potentially benefit vast
population of patients who suffer wide varieties of respiratory
diseases.
[Back to top]
New Agents for the Treatment of Tuberculosis on Clinical
Study Phases II/III
Marcus B. Conde and Margarita Elsa Villarino
Tuberculosis (TB) remains a serious global health problem.
The infrastructure necessary for delivering the TB treatment
regimens recommended for use today accounts for more than
two-thirds of the total cost of treating TB patients. Reducing
the duration of the treatment regimen from the currently recommended
six months to two months could result in significant cost
savings and make treatment available to more patients worldwide.
The objective of this review is to high-light potential new
agents for treatment of drug-susceptible TB disease that are
currently under study or were recently evaluated through clinical
trials. We conducted a literature search in the English language
for clinical studies as well as an electronic computer-assisted
and manual search. The literature search was conducted on
August 30, 2006, using MED-LINE (2000-2006), EMBASE (2000-2006)
and the National Institute of Health (NIH) Clinical Trials
Register database (2000-2006). Most of the new agents identified
as anti-TB drug candidates are still in the preclinical phases.
Only the diarylquinolines and the fluoroquinolones are being
evaluated for potential inclusion in new ultra-short TB treatment
regimens through clinical studies phases II/III. In this article,
we present a summary of the studies reviewed and discuss their
potential for modifying future treatment recommendations for
TB treatment.
[Back to top]
Clinical and Prognostic Implications of Cognitive
Dysfunction and Depression in COPD
Andrea Corsonello, Claudio Pedone and Raffaele Antonelli
Incalzi
In chronic obstructive pulmonary disease (COPD), cognitive
dysfunction - mainly of secondary memory, executive, and constructional
abilities - is a marker of disease severity with important
clinical and prognostic implications. It correlates with poor
compliance with pharmacological therapy, and poor compliance,
in turn, increases the cost/effectiveness ratio of home care
programs.
Executive dysfunction is associated with difficulty with inhaler
devices and should be systematically evaluated before prescribing.
Drawing impairment has been associated with mortality, although
the underlying neurologic abnormalities (right insular damage
with autonomic dysfunction or subcortical damage) remain to
be defined. Depression is also negatively correlated with
survival, besides being a risk factor for quitting respiratory
rehabilitation.
Cognitive dysfunction should always be considered among the
systemic effects of COPD and be the object of systematic screening
in COPD patients. Identifying cognitive impairment would prompt
either interventions promoting the adherence to the therapy
or further investigations to exclude respiratory (nocturnal
or effort hypoxemia, coexistent obstructive sleep apnoea)
or non respiratory (decompensated diabetes, hypoglycaemic
crises, poorly controlled hypertension etc.) causes of cognitive
dysfunction. Cognitive enhancing strategies deserve consideration
in the framework of a comprehensive approach aimed at improving
the health status of people with COPD.
[Back to top]
The Nature of Immunological Reaction in the Peripheral
Airways of Cigarette Smokers
Joanna Domagala-Kulawik
The influence of tobacco smoke on human health is still an
important problem worldwide. Complex inflammatory processes
and changes in the immune system are crucial in the pathogenesis
of smoking related disorders like chronic obstructive lung
disease (COPD), lung cancer, asthma, interstitial lung diseases
(ILD) and atherosclerosis. The objective of this review is
to present the alterations in the immune system in smokers.
Discrete changes in peripheral blood of smokers may be found,
such as leukocytosis and elevated proportion of T cells. However,
the mainly affected system is the respiratory tract. In bronchial
epithelium, metaplastic and dysplastic changes are accompanied
by elevated expression of adhesion molecules and secretion
of many proinflammatory cytokines. In the population of pulmonary
macrophages, an elevated proportion of cells, changes in expression
surface markers: CD14, CD54, CD11 and CD71 with impaired phagocytic
and antigen presenting function were observed. The influence
of tobacco smoke on the population of granulocytes results
in elevated proportion of neutrophils and eosinophils and
elevated concentration of the products of neutrophils: neutrophil
elastase (NE), interleukin- 8 (IL-8) and tumor necrosis factor
α (TNFα).
Tobacco smoke seems to alter the way of death of neutrophils
from apoptosis to necrosis. On the other hand, an elevated
expression of the receptors of apoptosis on lymphocytes was
found. Cigarette smoke enhances the recirculation of lymphocytes,
which results in the augmentation of activated and cytotoxic/
suppressor cells in the bronchial lumen.
Smoking cessation is the most effective method of prophylaxis
and treatment of diseases related to tobacco smoking. However,
many immunological changes in smokers are not completely reversible
after quitting smoking.
[Back to top]
Current Treatment of the Pulmonary Arterial Hypertension
Juan C. Gallego-Page
Pulmonary arterial hypertension is a feature of a spectrum
of diseases that includes elevated pulmonary vascular resistance,
induces right ventricular insufficiency and heart failure,
and threatens the life. The aetiology and pathogenesis is
diverse and associated with elevated morbidity and mortality.
Treatment is frequently deficient and empirical. Fortunately,
in recent years, randomized clinical trials have shown useful
effects of various drugs on pulmonary arterial hypertension.
This article reviews the pharmacological and not pharmacological
therapeutic options to treat pulmonary arterial hypertension
and attempts to provide a proposal of algorithm for its management
based upon the evidence and available guidelines for clinical
management.
[Back to top]
Prediction and Prevention of Abnormal Antenatal Lung
Growth
Michael Prendergast and Anne Greenough
Pulmonary hypoplasia, the result of abnormal antenatal lung
growth, occurs as a primary anomaly or more usually the consequence
of disorders resulting in reduction of amniotic fluid volume,
intra-thoracic space or fetal breathing movements. Two dimensional
(2D) ultrasound examination yields useful information on amniotic
fluid volume and the presence of congenital abnormalities
associated with pulmonary hypoplasia. Assessment of the thoracic
or lung size by 2D ultrasound examination, is insufficiently
specific, but a very low lung to head ratio predicts a fatal
outcome in fetuses with congenital diaphragmatic hernia (CDH).
Three-D ultrasound examination provides information on fetal
lung volume prior to 34 weeks of gestation but can be inaccurate
if there is oligohydramnios. Magnetic resonance imaging is
expensive and has limited patient acceptability. Antenatal
interventions attempted to prevent pulmonary hypoplasia include
amnio-infusion, which can facilitate ultrasound examination,
but only temporarily relieves oligohydramnios. Thoraco-amniotic
shunting results in effective drainage of pleural effusions,
facilitating resuscitation, but is usually performed too late
in pregnancy to influence lung growth. In utero surgical repair
of CDH has been attempted, but a more promising technique
is obstruction of the normal egress of fetal lung fluid by
placing a balloon in the trachea.
[Back to top]
The Role of Corticosteroids in Sepsis and Acute Respiratory
Distress Syndrome
MeiLan K. Han and Robert C. Hyzy
The use of corticosteroids in the treatment of critically
ill patients has been the subject of controversy for decades.
Information from recent clinical trials has helped to more
clearly define their use in the acute setting. Cortisol is
produced in response to pituitary corticortopin secretion
which is in turn released in response to hypothalamic corticorpin-releasing
hormone. Acute illness should result in increased cortisol
production, although relative corticosteroid insufficiency
can occur in sepsis and appears to be associated with increased
mortality. Despite this, diagnosing corticosteroid insufficiency
in patients with septic shock remains difficult. Investigators
have failed to find a reliable relationship between random
cortisol levels and mortality. However, recent evidence demonstrated
an increase of serum cortisol <9 mcg/dL following corticotropin
stimulation is associated with increased mortality from septic
shock. Corticosteroid replacement therapy in these patients
reduces mortality. The mortality benefit seen in this setting
may be limited to septic patients with acute respiratory distress
syndrome. Corticosteroids have been used in a variety of conditions
causing hypoxemic respiratory failure. While empiric steroids
were widely used to treat ARDS in the 1970’s and 1980’s,
more recent evidence from the ARDS clinical trial network
failed to demonstrate a mortality benefit, despite the fact
that patients were able to be weaned to unassisted breathing
more quickly. Tight glycemic control in ARDS patients receiving
corticosteroids can help avoid neuromyopathy and may afford
an opportunity to prevent a return to assisted breathing in
these patients. While steroids have also been reported for
use in the treatment of SARS, no trials have been performed
which support their efficacy.
[Back to top]
New Insights into the Biology of α1-Antitrypsin
and its Role in Chronic Obstructive Pulmonary Diseases
Sabina M. Janciauskiene, Tim Stevens and Ignacio Blanco
α1-antitrypsin,
an acute phase protein, is the prototypic member of the serpin
super family and a major inhibitor of serine proteases. As
an acute phase protein, α1-antitrypsin
is thought to play an important role in limiting host tissue
injury at sites of inflammation. The clinical importance of
α1-antitrypsin
is highlighted in individuals with inherited α1-antitrypsin
deficiency who exhibit an increased susceptibility to develop
chronic inflammatory conditions including chronic obstructive
pulmonary disease, systemic vasculitis and necrotizing panniculitis.
There is now an increasing evidence that α1-antitrypsin
may also exhibit biological activity independent of its protease
inhibitor function. Thus, conformationally modified and degraded
forms of α1-antitrypsin,
which lack antiprotease activity, demonstrate specific biological
effects in vitro and in vivo and highlight
the potentially broader modulatory role of α1-antitrypsin
in inflammatory diseases.
In this review we discuss the biological properties of α1-antitrypsin
and its role in chronic obstructive pulmonary diseases. A
more comprehensive understanding of the biology of native
α1-antitrypsin
and its modified forms may have a significant impact on our
understanding and ultimately treatment of disease pathologies
arising from both natural point mutations and from post-synthetically
modified byproducts of α1-antitrypsin.
[Back to top]
Role of Tyrosine Kinase Inhibitor Molecules in Non
Small Cell Lung Cancer: From Benchside to Bedside
Alessia Catassi, Alfredo Cesario, Pierluigi Granone and
Patrizia Russo
The human epidermal growth factor receptor (EGFR) biology
is not completely explained; however EGFR-targeting has formed
the basis of extensive and growing drug development. Inhibition
of receptor tyrosine kinase activity involved in the EGFR
signalling cascade is a fundamental mechanism for the use
of EGFR specific tyrosine kinase (TK) inhibitors exemplified
by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva).
Despite initially promising results in chemotherapy-resistant
patients with non small cell lung cancer (NSCLC), disappointing
results from phase III trials of gefitinib in NSCLC have been
of concern of some. When EGFR-targeting drugs were introduced
into the clinic, the specific targets affected in human tumors
were unknown. Recently, different studies reported that mutations
in the TK domain of EGFR are strongly associated with gefitinib-
or erlotinib-sensitivity in patients with NSCLC. This article
reviews the rationale for targeting EGFR by TK inhibitors,
the discovery of EGFR mutations and subsequent studies to
define the incidence, spectrum and functions of EGFR mutations.
This paper represents the effort of a lung cancer focused
translational research team made up of molecular biologists,
medical oncologists and thoracic surgeons. The final objective
is to achieve a comprehensive, but simple, review
of the current status of the shift from cytotoxic to molecularly
targeted therapy in lung cancer treatment potentially useful
in the planning of translational research trials.
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