Asthma Induced by Isocyanates: a Model of
Cristina E. Mapp, Piera Boschetto, Deborah Miotto, Edoardo De Rosa
Department of Clinical and Experimental Medicine, Section of Hygiene and Occupational Medicine, University of Ferrara
Developments in the understanding of causes and natural history of asthma induced by isocyanates
may allow improved preventive strategies for occupational asthma (OA), and may also lead to improved un-
derstanding of mechanisms involved in IgE-independent nonoccupational asthma. Studies of genetic mark-
ers in OA induced by isocyanates suggest that HLA class II genes, glutathione S-transferase and NAT1
genotypes may predispose to development of this type of OA. Specific IgE antibodies against isocyanates are
not always found in subjects with OA caused by isocyanates, leading most researchers to consider this type
of OA, as a model of IgE-independent asthma. Evidence for cell-mediated immunity in OA induced by iso-
cyanates has been provided by bronchoalveolar lavage, bronchial biopsy and induced sputum studies. The
pathology of this type of asthma is similar to that of nonoccupational asthma, with cells such as eosinophils
and T lymphocytes that exhibit signs of activation, and with thickening of the reticular layer of the basement
membrane. Animal studies have shown that isocyanate asthma is driven primarily by CD4+ T cells and is
dependent upon the expression of Th2 cytokines. However, animal models are not always reflective of hu-
man responses. OA induced by isocyanates similarly to nonoccupational asthma, is a multifactorial condi-
tion, and it is likely that complex gene-environment interactions play a role. Better understanding of these
interactions is important for affected workers, and also has potential relevance for nonoccupational asthma.
: isocyanates, asthma, genetics, environment, exposure
agents, such as isocyanates, the presence of specificIgE antibodies has been documented in only a small
OA has been suggested as a model of adult-onset
subset of affected workers (5). The absence of demon-
asthma (1, 2). The wide interest is justified because
strable specific IgE antibodies in subjects with OA in-
OA is estimated to account for approximately 15% of
duced by LMW agents has led to speculation about
the adult asthmatic population (3). In spite of the rec-
IgE-independent immunological or even nonim-
ognized harmful health effects of isocyanates, they are
munological mechanisms (6). An area of current in-
widely used in several industrialized countries and are
terest in isocyanate asthma is the possibility that this
the leading cause of OA. Thus, isocyanate-induced
type of OA may be driven by T-cell recognition of iso-
asthma is one of the most studied models of OA (4).
cyanates or isocyanate derivatives (7). To date, several
The mechanisms by which these chemicals can induce
lines of evidence indicate that cell-mediated immuni-
host sensitization and asthma development remain
ty (8, 9) and airway epithelium (4) are involved in the
unclear. Available information indicates that a classi-
pathogenesis of OA induced by exposure to iso-
cal IgE-dependent hypersensitivity mechanism occurs
for OA induced by high-molecular-weight (HMW)
A number of recent publications have provided
agents, while for most low-molecular-weight (LMW)
further understanding of OA induced by exposure to
C.E. Mapp, P. Boschetto, D. Miotto, E. De Rosa
isocyanates and findings will be grouped under the
following headings: animal studies of sensitization
DQB1*0503 confers susceptibility to asthma induced
and asthma, genetic studies, airway inflammation and
by toluene diisocyanate (TDI), whereas DQB1*0501
offers protection (26). However, one study did notfind associations between isocyanate asthma andHLA-DR or HLA-DQ alleles, but in this study, ac-
Animal studies of sensitization and asthma
curate phenotypes of the subjects included in thestudy were not provided (27). By contrast, HLA class
Experimental animal models of isocyanate asth-
I antigens and tumor necrosis factor α-308G are not
ma have been described in review articles (10, 11) and
associated with either susceptibility or protection to
in several original studies (12-20). A common finding
the development of TDI-induced asthma (28).
of these models is the demonstration of an immuno-
A feature of isocyanate asthma is the develop-
logical basis for the disease, including the involvement
ment of persistent airway inflammation (29). Oxida-
of T-helper type 1/2 responses as well as CD4 and
tive stress is a key component of this inflammation
CD8 T cells (21). Sensitized animals develop a specif-
(30). The superfamily of glutathione-S transferase
ic IgG and IgE antibody response, airway hyper-re-
(GST) is critical for protecting cells from oxidative
sponsiveness and inflammation accompanied by in-
stress products. Individuals may differ in their ability
creased expression of cytokines, similar to human dis-
to deal with an oxidant burden, and such differences
ease (22, 23). Moreover, dermal or respiratory expo-
are in part genetically determined (31).
sure may be important in the workplace for the devel-
Evidence of the involvement of GST has been
opment of sensitization, and pulmonary pathology as-
provided for workers exposed to TDI for 10 years or
sociated with isocyanates can vary depending upon
more. The frequency of the GSTP1 Val/Val
the exposure (i.e. low-level subchronic or high-dose
was lower in asthmatic and hyperresponsive subjects,
acute inhalation) (23). Another important finding is
and the protective effect of homozygosity for the
that sensitization can occur through subchronic in-
allele increases in proportion to the dura-
halation of vapor-phase diisocyanate at levels as low as
tion of exposure to TDI (32). Therefore, subjects lack-
20 ppb. Even if animal models are not always reflec-
ing this genotype may develop ongoing airway in-
tive of human responses, they provide increased un-
flammation and consequent airway remodeling, lead-
derstanding of sensitization to LMW agents, such as
Recently, it has also been shown that the N-
acetyltransferase (NAT1) slow acetylator genotypeposed an increased risk of isocyanate asthma (33, 34).
Any association between a genetic marker and risk ofdisease is relevant if findings of the study have been
The study of gene-environment interactions is
replicated. Asthma is a complex disease, and genetic
facilitated in OA because it is possible to give precise
susceptibility is one of the factors involved in this con-
occupational case definitions, to estimate exposure to
occupational sensitizers, and comparisons can bemade between affected workers and healthy workerswith similar exposures (24).
Airway inflammation and remodeling
Data obtained in studies on isocyanate asthma
indicate that major histocompatibility complex class II
The airway inflammation process is similar in
proteins are important factors for the specificity of the
IgE-dependent and IgE-independent asthma (36). In
response to isocyanates (25). HLA class II molecules
the airways, inflammatory cells are increased in num-
are highly polymorphic and therefore plausible candi-
ber and activated, resulting in the secretion of proin-
date genes that influence the development of a specif-
flammatory mediators and proteins (37, 38) with
harmful effects on epithelial cells. Along with these
nent disability, even after cessation of exposure (47).
findings, the thickening of the reticular basement
Improvement does continue over long time, although
membrane has been described (7). In isocyanate asth-
at a slower rate than in the first two years after cessa-
ma, the majority of T cells obtained from bronchial
tion of exposure. Important determinants of improve-
biopsy specimens of TDI asthmatics showed the CD8
ment are the total duration of exposure, the duration
phenotype and produced interferon-γ (IFN-γ) and in-
of symptoms, the severity of asthma, baseline lung
volumes and the degree of airway hyper-responsive-
A reasonable index of airway inflammation is
ness at the time of diagnosis. Most subjects with OA
eosinophilia, and eosinophil counts in sputum are use-
retain specific bronchial reactivity to the sensitizing
ful in OA induced by isocyanates (40). However, it is
agent (HMW agent) even two or more years after ces-
still unclear whether changes in sputum eosinophil
sation of exposure (48). Similarly, in OA induced by
count relate to airway hyper-responsiveness . Other
isocyanates, after removal from exposure, specific
studies have described an increase in neutrophils in
bronchial reactivity has been described (49, 50). One
sputum of subjects with isocyanate asthma (41, 42),
of the hypotheses for the persistence of OA after the
but their role should be further delineated. Non-inva-
end of exposure is the presence of airway inflamma-
sive methods of assessing airway inflammation includ-
tion that can be documented even years after cessation
ing analysis of induced sputum have been recently re-
of exposure (51, 52). A recent study that involved in-
viewed (43). The conclusions are that this non-inva-
duced sputum has shown an increase of eosinophils,
sive method is a valid and reproducible tool for study-
neutrophils, and their product myeloperoxidase, and
the neutrophil chemoattractant, IL-8, in subjects with
It is almost universally accepted that airway in-
persistent airway hyper-responsiveness many years af-
flammation is present in both OA and non-occupa-
ter the last exposure to both HMW and LMW agents
tional asthma, whereas the role of airway remodelling
(53). Authors concluded that airway inflammation is
in the disease remains controversial. It provides an ex-
the cause of persisting airway hyper-responsiveness
planation for many conditions observed in asthmatics
and asthmatic symptoms. Because sputum was not ex-
(44). However, for some investigators, the thickening
amined before cessation of exposure, the starting de-
of the airway wall protects against airway narrowing
gree of airway inflammation is lacking. The persis-
and attenuates airway reactivity in subjects with asth-
tence of airway inflammation in the absence of re-ex-
ma (45). It is also unclear whether, in adult asthma,
posure to the offending agent appears self-sustained.
airway inflammation occurs first and remodelling lat-
Recent data indicate that, in isocyanate asthma, expo-
er. In isocyanate asthma, 6 to 21 months after cessa-
sure to TDI can augment cytocheratin-19 expression
tion of exposure, the thickening of reticular layer of
from the bronchial epithelial cell, which may involve
the basement membrane, even if reduced, is still pre-
immune responses as an autoantigen to induce airway
sent, and it is therefore a marker of long-lasting struc-
inflammation in this common type of OA (54).
tural changes of the airway wall (46).
Available data indicate that both airway inflam-
mation and airway remodelling are present in OA in-
duced by isocyanates, but further research is needed toestablish their role in causing obstruction, airway hy-
per-responsiveness and chronic asthma.
agents remains controversial. Several lines of evidenceindicate that isocyanate-induced asthma is a multifac-torial disease involving genetic susceptibility, the im-
mune system, and airway epithelium. To elucidate themechanisms of OA induced by isocyanates, further re-
Numerous follow-up studies have shown that
search is needed on the molecular interactions be-
subjects with isocyanate asthma are left with perma-
tween these chemicals and human airway proteins.
C.E. Mapp, P. Boschetto, D. Miotto, E. De Rosa
15. Lee YC, Kwak YG, Song Ch. Contribution of vascular en-
dothelial growth factor to airway hyper-responsiveness and
Supported by the Ministry of University and Scientific
inflammation in a murine model of toluene diisocyanate-
Research, A.R.C.A. (Associazione per la Ricerca e la Cura del-
induced asthma. J Immunol
2002; 168 (79): 3595-600.
l’Asma), and by the Consorzio Ferrara Ricerche
16. Matheson JM, Lemus R, Lange RW, et al. Role of tumor
necrosis factor in toluene diisocyanate asthma. Am J RespirCell Mol Biol
2002; 27: 396-405.
17. Lee KS, Jin SM, Kim HJ, Lee YC. Matrix metalloprotease
inhibitor regulates inflammatory cell migration by reducingICAM-1 and VCAM-1 expression in a murine model of
1. Tarlo SM. Occupational asthma: a valid model for adult
toluene diisocyanate-induced asthma. J Allergy Clin Im-
asthma? Curr Opin Allergy Clin Immunol
2003; 3: 91-4.
2. Maestrelli P. Natural history of adult-onset asthma. Edito-
18. Lee KS, Jin SM, Kim SS, Lee YC. Doxycycline reduces
rial. Am J Respir Crit Care Med
2004; 169: 331-2.
airway inflammation and hyper-responsiveness in a murine
3. Balmes J, Becklacke M, Blanc P, et al. American Thoracic
model of toluene diisocyanate-induced asthma. J Allergy
Statement: Occupational contribution to the burden of
2004; 113: 902-9.
airway disease. Am J Respir Crit Care Med
2003; 167: 787-
19. Lee KS, Jim SM, Lee YC. Imbalance between matrix met-
alloproteinase-9 and tissue inhibitor of metalloproteinase-1
4. Liu Q, Wisnewski AV. Recent developments in diiso-
in toluene diisocyanate-induced asthma. Clin Exp Allergy
cyanate asthma. Ann Allergy Asthma Immunol
2003; 90 (5
20. Pauluhn J, Woolhiser MR, Bloemen L. Repeated inhala-
5. Karol MH, Tollerud DJ, Campbell TP, et al. Predictive value
tion challenge with diphenylmethane-4,4’-diisocyanate in
of airways hyper-responsiveness and circulating IgE for
brown Norway rats leads to a time-related increase of neu-
identifying types of responses to toluene diisocyanate inhala-
trophils in bronchoalveolar lavage after topic induction. In-
tion challenge. Am J Respir Crit Care Med
1994; 149: 611-5.
6. Sastre J, Vandenplas O, Park HS. Pathogenesis of occupa-
21. Matheson JM, Johnson VJ, Luster MI. Immune mediators
tional asthma. Eur Respir J
2003; 22: 364-73.
in a murine model for occupational asthma: studies with
7. Wisnewski AV, Herrick CA, Liu Q, et al. Human T-cell
toluene diisocyanate. Toxicol Sci
2005; 84: 99-109.
proliferation and IFN-production induced by hexame-
22. Plitnick LM, Loveless SE, Ladics GS, et al. Cytokine mR-
thylene diisocyanate. J Allergy Clin Immunol
NA profiles for isocyanates with known and unknown po-
tential to induce respiratory sensitization. Toxicology
8. Saetta M, Di Stefano A, Maestrelli P, et al. Airway mucos-
al inflammation in occupational asthma induced by toluene
23. Matheson JM, Johnson VJ, Vallyathan V, Luster MI. Ex-
diisocyanate. Am Rev Respir Dis
1992; 145: 160-8.
posure and immunological determinants in a murine mod-
9. Bentley AM, Maestrelli P, Saetta M, et al. Activated T-
el for toluene diisocyanate (TDI) asthma. Toxicol Sci
lymphocytes and eosinophils in the bronchial mucosa in
isocyanate-induced asthma. J Allergy Clin Immunol
24. Mapp CE. Genetics and the occupational environment.
Curr Opin Allergy Clin Immunol
2005; 5 (2): 113-8.
10. Redlich CA, Wisnewski AV, Gordon T. Mouse models of
25. Mapp CE, Newman Taylor A. Occupational asthma with
diisocyanate asthma. Am J Respir Cell Mol Biol
latency (Sensitizer-induced Occupational Asthma). Factors
predisposing to sensitization, development and persistence
11. Johnson VJ, Matheson JM, Luster MI. Animal models for
of symptoms. Proceedings of the First Jack Pepys Occupa-
diisocyanate-asthma: answers for lingering questions. Curr
tional Asthma Symposium. American Thoracic Workshop.
Opin Allergy Clin Immunol
2004; 4 (29): 101-10.
Am J Respir Crit Care Med
2003; 167: 454-7.
12. Mapp CE, Lucchini RE, Miotto D, et al. Immunization
26. Mapp CE, De Marzo N, Jovine L, et al. Association be-
and challenge with toluene diisocyanate decrease
tween HLA genes and susceptibility to toluene diiso-
tachykinin and calcitonin gene-related peptide immunore-
cyanate induced asthma. Clin Exp Allergy
2000; 5: 651-6.
activity in guinea pig central airways. Am J Respir Crit Care
27. Rihs HP, Barbalho-Krolls T, Huber H, Baur X. No evi-
dence for the influence of HLA class II alleles in iso-
13. Zheng KC, Nong DX, Morioko T, et al. Elevated inter-
cyanate-induced asthma. Am J Ind Med
1999; 32: 522-7.
leukin-4 and interleukin-6 in rats sensitised with toluene
28. Beghe’ B, Padoan M, Moss CT, et al. Lack of association of
diisocyanate. Ind Health
2001; 39: 334-9.
HLA class I genes and TNF-α-308 polymorphism in
14. Matheson JM, Lange RW, Lemus R, et al. Importance of
toluene diisocyanate-induced asthma. Allergy
2004; 59: 61-4.
inflammatory and immune components in a mouse model
29. Saetta M, Maestrelli P, Turato G. Airway wall remodelling
of airway reactivity to toluene diisocyanate. Clin Exp Aller-
after cessation of exposure to isocyanates in sensitized asth-
matic subjects. Am J Respir Crit Care Med
1995; 151: 489-94.
30. Elms J, Beckett PN, Griffin P, Curran AD. Mechanisms of
tion in occupational lung diseases. Curr Opin Allergy Clin
isocyanate sensitization. An in vitro approach. Toxicol in
44. Sont JK, Willems LN, Bel EH, et al. Clinical control and
31. Barnes PJ. Reactive oxygen species and airway inflamma-
histopathologic outcome of asthma when using airway hy-
tion. Free Radic Biol Med
1990; 9: 235-43.
per-responsiveness as an additional guide to long-term
32. Mapp CE, Fryer AF, De Marzo N, et al. Glutathione S-
treatment. Am J Respir Crit Care Med
1999; 159: 1043-51.
transferase GSTP1 is a susceptibility gene for occupational
45. Nimi A, Matsumoto H, Takemura M, Ueda T, Chin K,
asthma induced by isocyanates. J Allergy Clin Immunol
Mishima M. Relationship of airway wall thickness to air-
way sensitivity and airway reactivity in asthma. Am J Respir
33. Wikman H, Piirila P, Rosenberg C, et al. N-acetyltrans-
Crit Care Med
2003; 168: 983-8.
ferase genotypes as modifiers of diisocyanate exposure-as-
46. Turato G, Saetta M. Why does airway obstruction persist
sociated asthma risk. Pharmacogenetics
2002; 12: 227-33.
in asthma due to low-molecular-weight agents? Occup Med
34. Berode M, Jost M, Ruegger M, Savolainen H. Host factors
in occupational diisocyanate asthma: a Swiss longitudinal
47. Padoan M, Pozzato V, Simoni M, et al. Long-term follow-
study. Int Arch Occup Environ Health
2005; 78 (2): 158-63.
up of toluene diisocyanate-induced asthma. Eur Respir J
35. Mapp CE. The role of genetic factors in occupational asth-
ma. Eur Respir J
2003; 22: 173-8.
48. Lemiere C, Cartier A, Malo JL, Lehrer SB. Persistent spe-
36. Mapp CE. Occupational asthma. State of Art. Am J Respir
cific bronchial reactivity to occupational agents in workers
Crit Care Med
2005; 172: 280-305.
with normal nonspecific bronchial reactivity. Am J Respir
37. Maestrelli P, Di Stefano A, Occari P, et al. Cytokines in the
Crit Care Med
2000; 162: 976-80.
airway mucosa of subjects with asthma induced by toluene
49. Mapp CE, Chiesura Corona P, De Marzo N, Fabbri LM.
diisocyanate. Am J Respir Crit Care Med
1995; 151: 607-12.
Persistent asthma due to isocyanates: a follow-up study of
38. Maestrelli P, Occari P, Turato G, et al. Expression of inter-
subjects with occupational asthma due to toluene diiso-
leukin (IL)-4 and IL-5 proteins in asthma induced by
cyanate (TDI). Am Rev Respir Dis
1988; 137: 1326-9.
toluene diisocyanate (TDI). Clin Exp Allergy
50. Paggiaro PL, Bacci E, Dente FL, Talini D, Giuntini C.
Prognosis of occupational asthma induced by isocyanates.
39. Maestrelli P, Del Prete GF, De Carli M, et al. CD8 T-cell
Bull Eur Physiopathol Respir
1987; 23: 565-9.
clones produce interleukin-5 and interferon-γ in bronchial
51. Saetta M, Maestrelli P, De Marzo N, et al. Effect of cessa-
mucosa of patients with asthma induced by toluene diiso-
tion of exposure to toluene diisocyanate (TDI) on the
cyanate. Scand J Work Environ Health
1994; 20: 376-81.
bronchial mucosa of subjects with TDI-induced asthma.
40. Maestrelli P, Calcagni P, Saetta M, et al. Sputum
Am Rev Respir Dis
1992; 145: 169-74.
eosinophilia after asthmatic responses induced by iso-
52. Paggiaro PL, Bacci E, Paoletti P, et al. Bronchoalveolar
cyanates in sensitized subjects. Clin Exp Allergy
lavage and morphology of the airways after cessation of ex-
posure in asthmatic subjects sensitized to toluene diiso-
41. Lemiere C, Romeo P, Chaboillez S, Tremblay C, Malo JL.
1990; 98: 536-42.
Airway inflammation and functional changes after expo-
53. Maghni K, Lemiere C, Ghezzo H, Yuquan W, Malo JL.
sure to different concentrations of isocyanates. J Allergy
Airway inflammation after cessation of exposure to agents
2002; 110: 641-6.
causing occupational asthma. Am J Respir Crit Care Med
42. Park HS, Jung KS, Hwang SC, Nahm DH, Yim HE. Neu-
trophil activation following TDI bronchial challenges to
54. Choi JH, Nahm DH, Kim SH, et al. Increased levels of
the airway secretion from subjects with TDI-induced asth-
IgG to cytokeratin 19 in sera of patients with toluene di-
ma. Clin Exp Allergy
1999; 29: 1395.
isocyanate-induced asthma. Ann Allergy Asthma Immunol
43. Lemiere C. Non-invasive assessment of airway inflamma-
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