Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Effects of an enzyme agent containing mutanase and dextranase for treatment of biofilms in bacteria- and yeast-infected canine otitis externa.

The purpose of this study was to evaluate in detail both the in vivo and in vitro efficacy of the enzyme agents, ZYMOX® Plus Otic (ZYMOX-P), in the treatment of canine otitis externa (OE). Eight dogs with a diagnosis of non-seasonal severe chronic OE were recruited for the study. ZYMOX-P was administered for 2-4 weeks. The Otitis Index Score (OTIS3) and bacteria or yeast colony growth were measured. Also, minimum biofilm (BF) formation inhibition concentration (MBIC) and BF bactericidal concentration (BBC) were measured in vitro. OTIS3 showed a statistically significant reduction after treatment (88.2%, p⟨0.001; pre-treatment = 11.0 ± 0.9; post-treatment = 1.3 ± 0.4, mean ± SEM). The individual OTIS scores, erythema, edema, erosions/ ulcerations, exudate and pruritus showed significant reduction (85.7%, 95.7%, 83.3%, 80.0%, and 89.3%, respectively). Microscopic examination revealed the presence of BF exopolysaccharide in all 8 ear samples when stained with alcian blue. Seven of the 8 dogs (87.5%) showed a reduction in colony growth. ZYMOX-P was effective at 34-fold and 16-fold dilutions on MBIC and BBC, respectively. These findings indicate that ZYMOX-P has efficacy against BF-related infection and is beneficial when used for the management of canine OE.

IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype.

BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.

Cyclosporin A Treatment in Intrinsic Canine Atopic Dermatitis (Atopic-like Dermatitis): Open Trial Study.

In this study, dogs were separated into two groups and treated with immunosuppressant (Cyclosporin A: CsA). The first group was the canine atopic dermatitis (CAD) group, which is similar to extrinsic atopic dermatitis (AD) in humans (treated with a CsA dose of 2.5-5.5 mg/kg, n=8), and the second group was the canine atopic-like dermatitis (ALD) group, which is similar to intrinsic AD in humans (treated with a CsA dose of 2.5-6.5 mg/kg, n=14). The canine atopic dermatitis extent and severity index (CADESI)-4 was evaluated before treatment (PRE) and after treatment (POST) to assess the effectiveness of CsA for the two groups. In the CAD group, CADESI-4 showed no change (PRE:79±29, POST:77±28) and out of the eight dogs, no dogs showed complete remission, three dogs showed partial remission, and five dogs showed no effect. Whereas in the ALD group, CADESI-4 showed a significant reduction (PRE: 61±42, POST: 32±25, p<0.01) and out of the 14 dogs, 11 dogs showed complete remission, two dogs showed partial remission, and one dog showed no effect. The results indicate that the immunosuppressant showed effectiveness for the dogs diagnosed with ALD. One dog had to be treated for a year and eight months, which was the longest period in the study, this dog presented with hyperplasia of the lymphoidgland and mammary tumor.

Rush sublingual immunotherapy in canine atopic dermatitis: a prospective pilot study.

Twenty dogs with canine atopic dermatitis (CAD) were treated with rush sublingual immunotherapy (SLIT), with a 48 hour build-up phase and 6 months maintenance phase (treated by antigen once every 3-4 weeks). The canine atopic dermatitis extent and severity index (CADESI)-4 was evaluated before treatment (baseline) and after 6 months. An open, non-controlled, non-randomized pilot trial was conducted to assess the effectiveness and safety of rush SLIT for environmental allergen extracts (Dematophagoides pteronyssinus and D.farinae mix and other). Three dogs dropped out and 17 dogs finished the trial. CADESI-4 at baseline was 60.6±27.1 (range 17-107, n=17). After 6 months of SLIT treatment, CADESI-4 was 37.4±36.0 (range 5-152, n=17) (p<0.01), which was a 38.3% reduction. A significant improvement, defined as a CADESI-4 reduction of >30%, was observed in 13 out of 17 dogs (76%). A moderate improvement, defined as a CADESI-4 reduction of ≦30%, was observed in 2 dogs (12%). In the other 2 dogs (12%), CADESI-4 worsened or showed no change. However, no severe adverse effects were observed during the trial. Therefore, rush SLIT against environmental allergen extract for CAD showed effectiveness and safety as evidenced by the reduction of CADESI-4 after 6 months SLIT without severe adverse effects.

Quantitative Assessment of Circumferential Enhancement along the Wall of Cerebral Aneurysms Using MR Imaging.

BACKGROUND AND PURPOSE: The incidence of wall enhancement of cerebral aneurysms on vessel wall MR imaging has been described as higher in ruptured intracranial aneurysms than in unruptured intracranial aneurysms, but the difference in the degree of enhancement between ruptured and unruptured aneurysms is unknown. We compared the degree of enhancement between ruptured and unruptured intracranial aneurysms by using quantitative MR imaging measures. MATERIALS AND METHODS: We performed quantitative analyses of circumferential enhancement along the wall of cerebral aneurysms in 28 ruptured and 76 unruptured consecutive cases by using vessel wall MR imaging. A 3D-T1-weighted fast spin-echo sequence was obtained before and after contrast media injection, and the wall enhancement index was calculated. We then compared characteristics between ruptured and unruptured aneurysms. RESULTS: The wall enhancement index was significantly higher in ruptured than in unruptured aneurysms (1.70 ± 1.06 versus 0.89 ± 0.88, respectively; P = .0001). The receiver operating characteristic curve analysis found that the most reliable cutoff value of the wall enhancement index to differentiate ruptured from unruptured aneurysms was 0.53 (sensitivity, 0.96; specificity, 0.47). The wall enhancement index remained significant in the multivariate logistic regression analysis (P < .0001). CONCLUSIONS: Greater circumferential enhancement along the wall of cerebral aneurysms correlates with the ruptured state. A quantitative evaluation of circumferential enhancement by using vessel wall MR imaging could be useful in differentiating ruptured from unruptured intracranial aneurysms.

Fluoxetine (SSRI) treatment of canine atopic dermatitis: a randomized, double-blind, placebo-controlled, crossover trial.

This study investigated effects of a fluoxetine (selective serotonin reuptake inhibitors; SSRI, 1 mg/kg) on pruritus in canine atopic dermatitis (CAD). After 4-weeks of base-line observation, 8 dogs with CAD entered a 2-months randomized, double-blind, placebo-controlled, crossover trial comparing fluoxetine with placebo. Clinical efficacy was evaluated using a Canine Atopic Dermatitis Extent and Severity Index (CADESI-03) and Pruritus Visual Analog Scale (PVAS). Six dogs completed the study [two out of eight dogs (both of them were Shiba Inu) dropped out from the study due to a depression]. CADESI-03 and PVAS between fluoxetine and placebo showed no significant difference statistically (P > 0.05 and P > 0.05 respectively). Fluoxetine showed no efficacy on pruritus in CAD. Further researches are needed for the treatment on pruritus of CAD.

GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.

Low in situ expression of antioxidative enzymes in rat cerebellar granular cells susceptible to methylmercury.

Methylmercury (MeHg), an environmental neurotoxicant, induces site-specific toxicity in the brain. Although oxidative stress has been demonstrated with MeHg toxicity, the site-specific toxicity is not completely understood. Among the cerebellar neurons, cerebellar granule cells (CGCs) appear vulnerable to MeHg, whereas Purkinje cells and molecular layer neurons are resistant. Here, we use a MeHg-intoxicated rat model to investigate these cerebellar neurons for the different causes of susceptibility to MeHg. Rats were exposed to 20 ppm MeHg for 4 weeks and subsequently exhibited neuropathological changes in the cerebellum that were similar to those observed in humans. We first isolated the three cerebellar neuron types using a microdissection system and then performed real-time PCR analyses for antioxidative enzymes. We observed that expression of manganese-superoxide dismutase (Mn-SOD), glutathione peroxidase 1 (GPx1), and thioredoxin reductase 1 (TRxR1) was significantly higher in Purkinje cells and molecular layer neurons than in CGCs. Finally, we performed immunohistochemical analyses on the cerebellum. Immunohistochemistry showed increased expression of Mn-SOD, GPx1, and TRxR1 in Purkinje cells and molecular layer neurons, which was coincident with the mRNA expression patterns. Considering Mn-SOD, GPx1, and TRxR1 are critical for protecting cells against MeHg intoxication, the results indicate that low expression of these antioxidative enzymes increases CGCs vulnerability to MeHg toxicity.

The study of canine atopic dermatitis involving the isolation of dogs.

Twenty-seven pruritic dogs were used in this study. When a hypoallergenic diet was fed to these 27 dogs for six weeks, none of the dogs showed improvement of the pruritus. These dogs had a history and clinical signs of atopic dermatitis (AD) as defined by Prelaud's diagnostic criteria. Subsequently, the 27 dogs were isolated for observation for two weeks in the hospital. In the isolation room in the veterinary clinic, cages and tableware were all stainless steel, and carpet was not used. A hypoallergenic diet was continuously fed to the 27 dogs for two weeks, during which time they were kept in the isolation room. PVAS (Pruritus Visual Analog Scale) was performed prior to starting the isolation, at the start of the study and 2 weeks after starting the isolation. In 17 dogs (63%) the pruritus improved in the isolation room. A statistically significant reduction (p < 0.01) of PLS (Pruritus liners score) was recorded 2 weeks after isolation. It was hypothesized that the 17 dogs whose pruritus improved in the isolation room had AD caused by an environmental antigen that was not present in the isolation room. Pruritus of the remaining 10 dogs (37%) did not improve. For 6/10 dogs, the intradermal allergy testing was positive for an environmental antigen. For 4/10 dogs, the intradermal allergy testing was negative for all environmental antigens. Dogs for which sensitivity to an environmental antigen was not identified were thought to have atopic-like dermatitis.

Posterior circulation and high prevalence of ischemic stroke among young pediatric patients with Moyamoya disease: evidence of angiography-based differences by age at diagnosis.

BACKGROUND AND PURPOSE: At diagnosis, the primary clinical manifestations of pediatric Moyamoya disease are TIA or CSs. CSs are reported to be more prevalent in younger than in older children. We sought to determine whether age-related differences in clinical manifestations are associated with age-related angiographic differences. MATERIALS AND METHODS: We divided 78 patients diagnosed with Moyamoya disease before 16 years of age into four 4-year age groups and examined the relationships between age at diagnosis and clinical manifestations and angiographic and MR imaging findings. RESULTS: Among the 4 diagnostic age groups, in those younger than 4 years of age, the prevalence of CSs and of infarctions on MR images was highest, and along with severity of steno-occlusive lesions of the PCA, the prevalence was significantly higher than that in the next diagnostic age group (4-7 years), though the severity of steno-occlusive lesions in the ICA and the degree of transdural collaterals did not differ significantly. The prevalence of CSs and infarctions did not differ significantly in the 3 oldest diagnostic age groups, whereas ICA and PCA lesions and transdural collaterals correlated positively with diagnostic age. CONCLUSIONS: The high prevalence of CSs and infarctions in patients diagnosed before 4 years of age is associated with advanced steno-occlusive lesions of the PCA. In patients 4 years of age and older at diagnosis, transdural collaterals develop in parallel with advancement of ICA and PCA lesions, which may contribute to the nearly constant prevalence of CSs.

COX-2 inhibition attenuates cough reflex sensitivity to inhaled capsaicin in patients with asthma.

BACKGROUND AND OBJECTIVE: Cyclooxygenase (COX) is an enzyme that converts arachidonic acid to prostanoids. There are two isoforms of COX, namely COX-1 and COX-2. COX-2 is highly inducible by several stimuli and is associated with inflammation. Recent studies have shown that COX-2 is upregulated in the airway epithelium of patients with asthma but little is known about the role it plays in cough, a common symptom of bronchial asthma. This study was designed to investigate the role of COX-2 in cough reflex sensitivity in patients with asthma. PATIENTS AND METHODS: The effect of etodolac, a potent COX-2 inhibitor, on cough response to inhaled capsaicin was examined in 17 patients with stable asthma in a randomized, placebo-controlled crossover study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting 5 or more coughs, was measured as an index of airway cough reflex sensitivity. RESULTS: The geometric mean (geometric SEM) cough threshold was significantly increased after a 2-week treatment program with oral etodolac (200 mg twice a day) compared with placebo (36.7 [1.2] vs 21.6 [1.2] gM, P<.02). CONCLUSIONS: These findings indicate that COX-2 may be a possible modulator augmenting airway cough reflex sensitivity in asthmatic airways.

The leptomeningeal "ivy sign" on fluid-attenuated inversion recovery MR imaging in Moyamoya disease: a sign of decreased cerebral vascular reserve?

BACKGROUND AND PURPOSE: Moyamoya disease is an idiopathic occlusive cerebrovascular disorder with abnormal microvascular proliferation. We investigated the clinical utility of leptomeningeal high signal intensity (ivy sign) sometimes seen on fluid-attenuated inversion recovery images in Moyamoya disease. MATERIALS AND METHODS: We examined the relationship between the degree of the ivy sign and the severity of the ischemic symptoms in 96 hemispheres of 48 patients with Moyamoya disease. We classified each cerebral hemisphere into 4 regions from anterior to posterior. In 192 regions of 24 patients, we examined the relationship between the degree of the ivy sign and findings of single-photon emission CT, including the resting cerebral blood flow (CBF) and cerebral vascular reserve (CVR). RESULTS: The degree of the ivy sign showed a significant positive relationship with the severity of the ischemic symptoms (P < .001). Of the 4 regions, the ivy sign was most frequently and prominently seen in the anterior part of the middle cerebral artery region. The degree of the ivy sign showed a negative relationship with the resting CBF (P < .0034) and a more prominent negative relationship with the CVR (P < .001). CONCLUSIONS: The leptomeningeal ivy sign indicates decreased CVR in Moyamoya disease.

A case of masticatory disturbance incidental to trigeminal schwannoma: changes in occlusal force and masticatory sensation before and after radiosurgery.

We report here a case of masticatory disturbance evoked by trigeminal schwannoma, in which we have evaluated the changes in occlusal force and masticatory sensation before and after treatment for the tumour. The patient was a 43-year-old woman and her chief complaint was a loss of masticatory sensation on her left side. MR imaging revealed an enhanced tumour in the left cavernous sinus/Meckel's cave. The left masseter muscle function and occlusal force showed remarkable decreases before treatment; however, the sensory thresholds of her facial skin and dental pulp were not significantly different from the control side, indicating that her loss of masticatory sensation was not due to sensory disturbance but to occlusal force weakness. Gamma-knife radiosurgery resulted in a significant improvement in masticatory sensation following an increase in occlusal force.

Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA).

The aim of this study was to evaluate the usefulness of EGFR mutation status in serum DNA as a means of predicting a benefit from gefitinib (IRESSA) therapy in Japanese patients with non-small cell lung cancer (NSCLC). We obtained pairs of tumour and serum samples from 42 patients treated with gefitinib. EGFR mutation status was determined by a direct sequencing method and by Scorpion Amplification Refractory Mutation System (ARMS) technology. EGFR mutations were detected in the tumour samples of eight patients and in the serum samples of seven patients. EGFR mutation status in the tumours and serum samples was consistent in 39 (92.9%) of the 42 pairs. EGFR mutations were strong correlations between both EGFR mutation status in the tumour samples and serum samples and objective response to gefitinib (P<0.001). Median progression-free survival time was significantly longer in the patients with EGFR mutations than in the patients without EGFR mutations (194 vs 55 days, P=0.016, in tumour samples; 174 vs 58 days, P=0.044, in serum samples). The results suggest that it is feasible to use serum DNA to detect EGFR mutation, and that it's potential as a predictor of response to, and survival on gefitinib is worthy of further evaluation.

Expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) in cerebral cavernous malformations: immunohistochemical analysis of MMP-2, -9 and TIMP-2.

OBJECT: Hemorrhage from cerebral vascular malformations such as cerebral cavernous malformation (CCM) can result in significant mortality and morbidity, but its underlying mechanism is undetermined. Excessive degradation of the vascular matrix by matrix metalloproteinases (MMPs), proteolytic enzymes that degrade all the components of extracellular matrix, can lead to instability of the vascular structure and can thereby cause bleeding. Thus we examined the expression of MMPs and tissue inhibitors of metalloproteinase (TIMP) in CCM. PATIENTS AND METHODS: We performed immunohistochemistry for MMP-2, -9, and TIMP-2 using Paraffin-embedded sections of the surgical specimens obtained from seven patients with CCM. All patients had a history of hemorrhage from CCM. FINDINGS: In all patients (7/7, 100%), MMP-2 and -9 were strongly expressed in endothelial cells of CCMs. Endothelial expression of TIMP-2 was also evident in all seven patients. In contrast, MMP-2, -9 and TIMP-2 were not identified in adjacent normal brain tissue. CONCLUSION: We found that CCM showed the increased endothelial expression of MMP-2, -9, and TIMP-2. Endothelial expression of MMPs and/or TIMP may affect the vascular matrix stability, and thus can contribute to hemorrhage from CCM.

Cloning and characterization of six highly similar endo-1,3-beta-glucanase genes in hexaploid wheat.

Pathogenesis-related (PR) proteins are often used as a marker of plant defense reactions. Some endo-1,3-beta-glucanase (Gns) genes encode proteins that belong to the PR protein family 2 (PR-2). Although the number of homologous family member genes is significantly greater in hexaploid wheat (Triticum aestivum L.) compared to other model plants, earlier studies did not evaluate the possible contribution of their homologs to hybridization signals in Northern blot analysis. In this study, we have examined whether routine transcriptional analyses of a PR gene is of high reliability or not by isolating six highly similar Gns genes (TaGlb2a, TaGlb2b, TaGlb2c, TaGlb2d, TaGlb2e, and TaGlb2f) and characterizing their expression patterns in detail. While TaGlb2b was shown to be a PR-2 gene, transcription of TaGlb2c and TaGlb2d was not induced upon infection with either powdery mildew (Erysiphe graminis) or head blight (Fusarium graminearum) pathogens; their transcripts were most abundant in healthy spikes (lemmas and in particular paleae). Therefore, in some cases, the conventional analyses do not necessarily provide accurate information on expression pattern of a PR gene in hexaploid wheat. This is also the first report of wheat genes that are specifically expressed in lemma/palea tissues of flowering spikelets.

Role of intercellular adhesion molecule-1 in a murine model of toluene diisocyanate-induced asthma.

BACKGROUND: Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) are thought to contribute to the airway inflammation and airway hyper-responsiveness (AHR) of allergic asthma. Some differences from allergic asthma have been noted, including airway neutrophilia, and the involvement of ICAM-1 in toluene diisocyanate (TDI) asthma is currently unclear. OBJECTIVE: We utilized mice lacking ICAM-1 expression (ICAM-1(-/-)) to investigate the role of ICAM-1 in airway inflammation and AHR in TDI-induced asthma. METHODS: Male C57BL/6J mice (ICAM-1(+/+)) and ICAM-1(-/-) mice were intranasally sensitized to TDI solution or solvent alone. Airway inflammation, AHR and cytokine secretion were assessed 24 h after challenge by TDI or solvent. The production of antigen-specific IgG and IgE by TDI sensitized and non-sensitized mice was determined. RESULTS: TDI challenge to ICAM-1(+/+) mice induced an increase in airway inflammatory cell numbers, AHR and cytokine secretion of TNF-alpha, macrophage inflammatory protein-2 (MIP-2), IL-4, IL-5 and IFN-gamma into the bronchoalveolar lavage fluid. All these pathophysiological changes were reduced in ICAM-1(-/-) mice. Serum levels of TDI-specific IgG and IgE of ICAM-1(-/-) and ICAM-1(+/+) mice were comparable. CONCLUSION: These results suggest that ICAM-1 plays an essential role in airway inflammation and AHR in TDI-induced asthma.