Allergic Rhinitis, Asthma, Airway Biology, and Chronic
Obstructive Pulmonary Disease in AJRCCM in 2004
Leonardo Fabbri, Stephen P. Peters, Ian Pavord, Sally E. Wenzel, Stephen C. Lazarus, William MacNee,
Franc ¸ois Lemaire, and Edward Abraham
Medical, Oncological, and Radiological Sciences, University of Modena, Modena, Italy; Center for Human Genomics, Wake Forest University
School of Medicine, Winston-Salem, North Carolina; Department of Respiratory Medicine and Thoracic Surgery, Glenfield Hospital,
Leicester, United Kingdom; National Jewish Medical and Research Center, Department of Medicine and Division of Pulmonary Sciences and
Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado; Division of Pulmonary and Critical Care Medicine,
University of California–San Francisco, San Francisco, California; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh,
Scotland, United Kingdom; AP-HP, Reanimation Medicale, Ho ˆpital Universitaire Henri Mondor, Creteil, France
ALLERGIC RHINITIS AND NASAL DISORDERS
The eosinophil, found commonly in tissue in asthma, allergic
rhinitis, and nasal polyposis, is generally believed to be cleared
cytosis. Uller and coworkers (1) used histochemical and ultra-
structural techniques to examine human nasal polyp tissue and
peripheral blood eosinophils for apoptosis, secondary necrosis,
and cytolysis. They found that apoptotic eosinophils are exceed-
ingly rare in human nasal polyp tissue. Although macrophages
were seen commonly in tissue, histochemical techniques and
transmission electron microscopy did not suggest engulfment of
eosinophils. They found evidence that eosinophils migrate be-
tween epithelial cells into the airway lumen and that proinflam-
matory disintegration through cytolysis occurs as a primary event.
diseased airways occurs through pathways other than apoptosis,
including paraepithelial migration and cytolysis.
Inflammation and Hyperreactivity
Watanabe and coworkers (2) raised the question of whether
there might be other targets for therapeutic antibodies in a study
of laboratory mice deficient in the IgG Fc receptor Fc?R11B.
eosinophilia after allergen challenge than wild-type mice. This
was associated with reduced interleukin 4 (IL-4) production by
nasal mononuclear cells and decreased generation of allergen-
induced IgE. These effects were not mice strain–specific and were
independent of the route and type of sensitization. The authors
suggested that modulation of expression and/or function of
Fc?R11B might be a useful tool to inhibit allergic inflammation.
Suissa and coworkers (3) assessed the clinical relevance of the
systemic effect of inhaled and nasal corticosteroids in a nested
case-control study with the particular merit of carefully control-
ling for oral corticosteroid use. The authors found no evidence
increased fracture risk and that the risk of hip fracture was
only increased in long-term users of more than 2,000 ?g/day of
beclomethasone or equivalent.
Correspondence and requests for reprints should be addressed to Edward Abra-
ham, M.D., University of Colorado Health Sciences Center, Division of Pulmonary
Sciences and Critical Care Medicine, 4200 East 9th Avenue, Box C272, Room
5503, Denver, CO 80262-0001. E-mail: firstname.lastname@example.org
Am J Respir Crit Care MedVol 171. pp 686–698, 2005
Internet address: www.atsjournals.org
ASTHMA AND AIRWAY BIOLOGY
Why some patients with asthma require high-dose corticosteroid
therapy and others continue to have refractory symptoms is an
important question. In vitro, corticosteroid insensitivity can be
induced in peripheral blood mononuclear cells by IL-2 and IL-4,
suggesting that the inflammatory milieu might be important.
Torrego and coworkers (4) showed that this phenomenon was
not related to an increased expression of the inhibitory cortico-
steroid receptor GR-? in peripheral blood mononuclear cells
Interestingly, peripheral blood mononuclear cells from subjects
with unstable asthma had increased mRNA for the active gluco-
corticoid receptor GR-?, but demonstrated a reduced antiprolif-
erative effect of dexamethasone, suggesting impaired function of
GR-?. The authors speculated that this effect reflects IL-2– and
IL-4–induced activation of the p38 mitogen-activated protein ki-
nase, resulting in phosphorylation of GR and reduced glucocorti-
coid binding affinity and nuclear translocation of the GR.
Recent evidence suggests that alterations in the helper T-cell
type 1 (Th1) cytokine pathway may be associated with suscepti-
bility to allergic asthma. Birkisson and colleagues (5) examined
a number of genes and protein expression in the Th1 pathway
involved with IL-12 and IFN-?, their subunits, and receptors,
and found no evidence for a defect in these cytokine genes and
responses as a primary event in asthma.
The IL-1 cluster on the human chromosome 2q12-2q14 has
promising candidate genes for asthma and other inflammatory
diseases. Gohlke and coworkers (6) conducted a study of single-
nucleotide polymorphisms (SNPs) and found the diagnosis of
asthma to be associated with SNPs in the IL-1 receptor antago-
nist and transforming growth factor ?1(TGF-?1) genes, respec-
TGF-?1is increased in the lungs of individuals with asthma
and may modulate airway inflammation and remodeling. Sil-
verman and colleagues (7) performed a case-control study of
527 patients with asthma and 170 without asthma. In the case
of TGF-?1, the T allele of C-509T was not only associated with
a diagnosis of asthma but also appeared to enhance gene tran-
scription. Genes involved in the innate immune system were
Toll-like receptor 10 is a potential asthma candidate gene,
because in early life, innate immune responses to inhaled aller-
gens and pathogen-associated molecular patterns may influence
asthma susceptibility. Lazarus and colleagues (8) reported that
two SNPs in Toll-like receptor 10 were associated with asthma in
two different populations (Nurses’ Health Study and Childhood
Asthma Management Program).
Year in Review687
In a case-control analysis, Hizawa and colleagues (9) exam-
ined the genetic influence of promoter polymorphisms on the
development of atopy and asthma in a Japanese population
(n ? 584). The authors reported that two different functional
variations in the macrophage migration inhibitory factor (MIF)
associated with atopy but not asthma.
Genome scans for asthma have identified suggestive or sig-
nificant linkages on 17 different chromosomes, including chro-
mosome 12, region q13-23, housing the vitamin D receptor
(VDR) gene. Poon and colleagues (10) reported that six variants
of the vitamin receptor gene falling into two haplotype blocks
were associated with asthma and four variants were associated
with atopy in a Quebec cohort.
VDR polymorphisms have been associated with several im-
mune-related diseases, and VDR and vitamin D itself modulate
T-cell differentiation. VDR maps to chromosome 12q, near a
region commonly linked to asthma.
Raby and colleagues (11) evaluated VDR as part of a 12q
positional candidate survey and in response to observations of
VDR polymorphism associating with asthma and atopy in a
founder population of Quebec. Four of six variants were associ-
ated with asthma. Interestingly, and confusingly, one of these
frequency in a second cohort (517 females with asthma and 519
matched control subjects), but the association was reversed (i.e.,
appeared to confer protection rather than risk). Clearly, the
are complex and not well understood.
Burchard and colleagues (12) explored lung function, broncho-
dilator response, and asthma severity in subjects of Puerto Rican
and Mexican ethnicity. They discovered that Puerto Rican indi-
viduals with asthma had reduced lung function, bronchodilator
responsiveness (to albuterol), more severe asthma with greater
morbidity, and longer asthma duration than Mexican individuals
with asthma. These findings underscore the importance of racial/
ethnic factors in asthma morbidity and response to therapy.
Glutathione is an antioxidant that mitigates oxidative stress in
the lung. Acetaminophen results in a dose-dependent decrease
in levels of glutathione in the lungs. Barr and colleagues (13),
in a prospective cohort study of 121,700 women in the Nurses’
Health Study, examined the relationship between use of acet-
aminophen and the development of adult-onset asthma. Partici-
pants were queried about the frequency of acetaminophen use
in 1990. Those who reported physician-diagnosed asthma on
questionnaires completed in1990–1996 and in 1998were defined
as new cases. During 352,719 person-years of follow-up, there
ophen use was positively associated with newly diagnosed asthma
(p ? 0.006). The authors suggested that the historical trends in
analgesic use may be responsible, in part, for the population-
level increases in asthma prevalence in the United States.
States, and epidemiologic data suggest that obesity may be a
risk factorfor asthma.In areport ofan NHLBIworkshop, Weiss
and Shore (14) summarized epidemiologic and pathophysiologic
research linking obesity and asthma, and suggested future direc-
tions for research.
Animal models. The importance of Th2 cytokines in acute mouse
models of allergic asthma is supported by numerous studies.
However, a similar level of importance of Th2 cytokines in hu-
man asthma has not yet been demonstrated. A study by Kumar
and colleagues (15) suggests that Th1 cytokines, such as IFN-?,
this chronic disease model, anti–IL-5 was effective in improving
elements of remodeling and eosinophil infiltration, whereas
IL-13 impacted goblet cell hyperplasia with a minor effect on
airway reactivity. However, ? interferon decreased total cellular
inflammation and significantly reduced airway hyperresponsive-
ness. Studies looking at combinations of antibodies were not
performed. These studies suggest that Th1 cytokines, in addition
to Th2 cytokines, may be important in producing phenotypic
changes in mice similar to those seen in asthma.
There is a need for alternative management strategies in
patients whose asthma is inadequately controlled on inhaled
corticosteroids. Toward and colleagues (16) examined two mod-
LPS or sensitized guinea pigs with atopy exposed to ovalbumen.
and LPS-induced airway hyperresponsiveness and inflammatory
cell influx by a mechanism that appeared to be independent of
endogenous nitric oxide. The authors call for clinical trials of
phosphodiesterase-5 inhibitors in asthma and chronic obstruc-
tive pulmonary disease (COPD).
Infection with respiratory syncytial virus (RSV) has been
associated with wheezing and childhood asthma, together with
increased mucus production. In a murine model of prolonged
airway responsiveness induced by RSV in animals that had aller-
gic sensitization with ovalbumin, Hashimoto and colleagues (17)
measured the expression of the mucin production genes Muc-
5ac and gob-5 by histochemical analysis of lung tissue stained
with antimucin antibodies and Western blot analysis to deter-
mine the mechanisms by which RSV infection induces airway
hyperresponsiveness. Animals infected with RSV only had little
expression of the two mucin production genes, whereas animals
sensitized with ovalbumin and exposed during 5 days had in-
creased expression, which was enhanced by concomitant RSV
infection, but not inoculation with inactivated RSV. IL-10 levels
were not associated with mucin production. However, increased
lung levels of IL-17 after Day 5 were associated with increased
expression of mucin genes in sensitized mice, but not in animals
with RSV infection only. The results suggest that RSV infection
in the presence of allergic inflammation may worsen airway re-
sponsiveness via increased expression of mucus production genes.
Bronchial and bronchoalveolar specimens. As identified by
other studies, the vascular basis of asthma is a research priority.
Interest in this area is likely to be increased by the work of
Kanazawa and colleagues (18) showing that vascular endothelial
growth factor (VEGF) and the vascular permeability index were
philic bronchitis. This difference is potentially of fundamental
importance because eosinophilic bronchitis is associated with
that characterizes asthma.
Elliot and colleagues (19) studied isolated aggregations of
lymphoid cells in the cartilaginous airways from postmortem
tissues of nonsmokers and smokers, and nonfatal and fatal cases
of asthma. These aggregations of lymphocytes were present in
to the outer airway wall in 80% of cases. However, aggregates
with an area greater than 0.1 mm2were present more often in
both groups of patients with asthma, whereas vascular structures
weremorecommon incasesoffatalasthma. Airwayswithaggre-
of eosinophils and lymphomononuclear cells. The role played
Year in Review 697
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