PMID- 16195208
OWN - NLM
STAT- MEDLINE
DCOM- 20060103
LR  - 20191026
IS  - 0895-8378 (Print)
IS  - 0895-8378 (Linking)
VI  - 17
IP  - 13
DP  - 2005 Dec 1
TI  - Brown Norway rat asthma model of diphenylmethane 4,4'-diisocyanate.
PG  - 729-39
AB  - Allergic asthma is a complex chronic inflammatory disease of the airways and its 
      etiology is multifactorial. It involves the recruitment and activation of many 
      inflammatory and structural cells, all of which release inflammatory mediators 
      that result in typical pathological changes of asthma. The features of asthma 
      addressed in this Brown Norway (BN) rat animal model include an analysis of 
      cellular infiltrations in the lung, inflammatory factors in bronchoalveolar 
      lavage (BAL), total immunoglobulin E (IgE) production in serum, and changes in 
      delayed-onset respiratory reactions upon four inhalation challenges (every 2 wk) 
      with polymeric diphenylmethane diisocyanate (MDI) aerosol in two groups of 
      topically sensitized rats. The dependence on the induction-related variables was 
      analyzed by using almost identical surface area doses but different total doses 
      per animal. This regimen caused acute exacerbations of delayed-onset respiratory 
      reactions, for which intensity increased with each challenge. After the fourth 
      challenge BAL neutrophils, lymphocytes, eosinophils, cell counts, protein, and 
      lactate dehydrogenase (LDH) as well as lung weights were significantly increased 
      in sensitized rats relative to naive but challenged controls. Histopathology 
      revealed activated bronchial lymphatic tissue, increased recruitment of 
      inflammatory cells, the beginning of peribronchial/peribronchiolar fibrosis, 
      thickening of alveolar septae, and vascular hypertrophy. Total IgE in serum was 
      significantly increased in sensitized rats. Thus, high-dose topical induction to, 
      and repeated inhalation challenges with, MDI was associated with a marked 
      neutrophilic and a less consistent eosinophilic inflammatory response. With 
      regard to the relative sensitivity of endpoints, those that integrate 
      independently a series of complex physiological events appeared to be most 
      practical to probe positive responses in this animal model. These include 
      postchallenge changes in Penh to identify respiratory responses delayed in onset 
      as well as inflammatory changes in BAL. In summary, this extension of a previous 
      study that used 16 mg MDI/m(3) instead of 39 mg MDI/m(3) that was used in the 
      current study for challenge exposures demonstrates that protocol variables are 
      most critical for the outcome of test. Moreover, the sensitivity of this bioassay 
      to define the typical asthma phenotype can be markedly improved by measurements 
      of respiratory responses delayed in onset rather than immediate in onset. 
      Accordingly, to increase the efficacy of this asthma model moderately irritant 
      concentrations of the hapten have to be used for challenge and at least three to 
      four adequately spaced challenge exposures are required to elicit a typical 
      asthma phenotype.
FAU - Pauluhn, Jurgen
AU  - Pauluhn J
AD  - Bayer HealthCare, Wuppertal, Germany. juergen.pauluhn@bayerhealthcare.com
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Inhal Toxicol
JT  - Inhalation toxicology
JID - 8910739
RN  - 0 (Irritants)
RN  - 0 (Isocyanates)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - B0LO6BBS8C (4,4'-diphenylmethane diisocyanate)
SB  - IM
MH  - Administration, Inhalation
MH  - Animals
MH  - Asthma/*physiopathology
MH  - Bronchoalveolar Lavage/veterinary
MH  - *Disease Models, Animal
MH  - Humans
MH  - Hypersensitivity
MH  - Immunoglobulin E/analysis
MH  - Inflammation
MH  - Irritants/toxicity
MH  - Isocyanates/administration & dosage/*toxicity
MH  - Lung/immunology/pathology
MH  - Rats
EDAT- 2005/10/01 09:00
MHDA- 2006/01/04 09:00
CRDT- 2005/10/01 09:00
PHST- 2005/10/01 09:00 [pubmed]
PHST- 2006/01/04 09:00 [medline]
PHST- 2005/10/01 09:00 [entrez]
AID - G372P13770198518 [pii]
AID - 10.1080/08958370500224631 [doi]
PST - ppublish
SO  - Inhal Toxicol. 2005 Dec 1;17(13):729-39. doi: 10.1080/08958370500224631.