Pneumoconiosis Caused by Inhalation of Metallic Titanium Grindings.

A 61-year-old man was referred to our hospital with dyspnea and an abnormal lung shadow. His occupational history, pathological findings, and an elemental analysis led to a definitive diagnosis of pneumoconiosis induced by titanium grindings. The patient experienced gradual improvement solely by avoiding titanium grindings. Titanium-induced lung disease is very rare, and most of these cases are caused by inhalation of titanium dioxide (TiO2), which is included in a wide range of commercially available products, such as paints, pigments, and cosmetics. However, industrial workers can also develop lung diseases due to the inhalation of metallic titanium materials during metal grinding.

Treatment of asthma in smokers: A questionnaire survey in Japanese clinical practice.

BACKGROUND: Cigarette smoking in patients with asthma leads to poor symptom control. As patients who are current smokers have been excluded from enrollment in many clinical trials on asthma, there are few reports on the treatment in current smokers with asthma. In this study, we aimed to assess how respiratory physicians manage asthma in current smokers in Japan. METHODS: Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma. RESULTS: The mean patient age was 61.1 years, and 62.9% of the patients were female. A total of 102 patients (5.8%) were current smokers, and 546 patients (31.1%) were former smokers. Long-acting muscarinic antagonists (LAMA) were prescribed more frequently for current smokers with asthma than for former smokers and never smokers with asthma (10.8% vs 4.6%, p = 0.01, 10.8% vs 3.8%, p < 0.01). In contrast, macrolides were prescribed more frequently for former smokers and never smokers with asthma than for current smokers with asthma (7.7% vs 1.0%, p = 0.01, 6.4% vs 1.0%, p = 0.03). Triple therapy, i.e., inhaled corticosteroids, long-acting beta agonists, and LAMA concomitantly, was prescribed for current smokers with asthma more frequently than for former smokers and never smokers with asthma (9.8% vs 4.0%, p = 0.01, 9.8% vs 3.3%, p < 0.01). CONCLUSIONS: According to this survey, current smokers with asthma received more intensive therapy, including LAMA, than did former smokers with asthma.

The immune checkpoint molecule VISTA regulates allergen-specific Th2-mediated immune responses.

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint receptor and ligand that regulates T-cell activation. We investigated the functional involvement of VISTA in Th2 cell-mediated immune responses using an ovalbumin (OVA)-induced allergic asthma model. Treatment with an anti-VISTA monoclonal antibody (mAb) during allergen sensitization increased the production of antibodies, including total IgE, OVA-specific IgG1 and IgG2a and allergen-specific IL-5 and IL-13; it also increased the expression of IL-13 by splenic CD4+ T cells. However, treatment with the anti-VISTA mAb during sensitization did not accelerate asthmatic responses, including airway hyper-responsiveness (AHR) or the number of eosinophils in bronchoalveolar lavage (BAL) fluid. In contrast, treatment with the anti-VISTA mAb during allergen challenge significantly augmented AHR and BAL fluid eosinophilia. This treatment also increased the production of IL-5 and IL-13 in BAL fluid and the expression of IL-13 by CD4+ T cells in draining lymph nodes. These results suggest that VISTA is involved in the regulation of Th2 cell generation and Th2 cell-mediated antibody production and regulates asthmatic responses, especially in the effector phase.

The TLR4-TRIF pathway can protect against the development of experimental allergic asthma.

The Toll-like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin-1 receptor and resistance protein (TIR) domain-containing adaptor inducing interferon-ß (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4+ ICOS+ T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild-type (WT), Trif-/- or Myd88-/- mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF-dependent and MyD88-independent. TRIF deficiency diminished the CD4+ ICOS+ T-cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF deficiency reduced the proportion of cervical lymph node and lung CD4+ ICOS+ Foxp3- cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin-induced CD4+ ICOS+ cells in the TRIF-dependent inhibition of airway hyper-responsiveness. Hence, our data demonstrate that stimulation of the TLR4-TRIF pathway can protect against the development of allergic airway disease and that a TRIF-dependent adjuvant effect on CD4+ ICOS+ T-cell responses may be a contributing mechanism.

Interstitial changes in asthma-COPD overlap syndrome.

INTRODUCTION: Asthma-COPD overlap syndrome (ACOS) is the widely recognized syndrome of asthma and COPD coexisting together. Cigarette smoking is a known risk factor for ACOS and is reported to be associated with interstitial lung diseases (ILDs). Subclinical ILDs have been frequently detected in smokers' lungs by radiological and pathological examinations. This finding raises the possibility that unrecognized mild interstitial changes take place in lungs with ACOS. OBJECTIVES: We sought to determine whether interstitial changes were present in the lungs of patients with ACOS and to characterize the clinical features of ACOS with interstitial changes. METHODS: Thirty patients with ACOS were enrolled in the study (26 men and 4 women, mean age 70.1 years). Interstitial changes in the lungs were estimated by high-resolution computed tomography (HRCT). Clinical findings and airway wall thickness on HRCT were assessed retrospectively and compared between ACOS patients with and without interstitial changes. RESULTS: Interstitial changes were found in seven patients (23.3%) with ACOS who had HRCT. The age and smoking amount were significantly higher in ACOS with interstitial changes than in ACOS without interstitial changes. ACOS with interstitial changes tended to have a higher rate of fungal sensitisation. Multivariate analysis showed pack-years were significantly related to the presence of interstitial changes. Airway walls assessed by HRCT were significantly thicker in ACOS with interstitial changes than in ACOS without interstitial changes. CONCLUSIONS: The ACOS patients with interstitial changes were heavier smokers and had thicker airway walls on HRCT compared to the ACOS patients without interstitial changes.

Chronic Hypersensitivity Pneumonitis With a Usual Interstitial Pneumonia-Like Pattern: Correlation Between Histopathologic and Clinical Findings.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by the inhalation of environmental antigens. The relationship between clinical, radiologic, and histopathologic findings of chronic HP remains unclear. METHODS: Sixteen patients with proven chronic bird-related HP with a usual interstitial pneumonia-like pattern were analyzed retrospectively. Histopathologic findings were semiquantitatively assessed and compared with clinical and radiologic findings. We also evaluated the histopathologic findings affecting prognosis. RESULTS: The extent of centrilobular fibrosis was negatively correlated with Pao2 (r = -0.55, P = .03). The extent of bridging fibrosis was positively correlated with the ratio of maximal expiratory flow at 50% of forced vital capacity to that at 25% (r = 0.60, P = .02). Patients with a greater extent of fibroblastic foci (FF) had more radiologic reticulation (P = .01), honeycombing (P = .01), and traction bronchiectasis (P = .02), and had significantly shorter survival time (P = .01) than patients with a lesser extent of FF. Multivariate analysis showed that the extent of FF was a significant prognostic factor (hazard ratio, 2.36; 95% confidence interval, 1.02-5.48; P = .04). CONCLUSIONS: Our findings demonstrated that the extent of FF was significantly associated with reticulation, honeycombing, and traction bronchiectasis on high-resolution CT scanning. Moreover, the extent of FF could be a useful predictor of mortality in chronic HP with a usual interstitial pneumonia-like pattern.

Fragmented gelsolins are increased in rheumatoid arthritis-associated interstitial lung disease with usual interstitial pneumonia pattern.

BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) occurs in 10%-30% of patients with RA, and interstitial lung disease (ILD) is associated with increased mortality in up to 10% of patients with RA. The pathogenesis of RA-ILD is virtually unknown. The aim of this study is to investigate the proteins related to UIP pattern by comparing to OP pattern in RA-ILD using proteome analysis of bronchoalveolar lavage fluid (BALF). METHODS: Proteomic differences in BALF were compared between the UIP pattern and OP pattern by examining BALF from 5 patients with the UIP pattern and 7 patients with the OP pattern by two-dimensional gel electrophoresis and mass spectrometry. RESULTS: In individual comparisons of BALF samples, the levels of the protein gelsolin and Ig kappa chain C region were significantly higher in the UIP pattern than in the OP pattern. In contrast, the levels of α-1 antitrypsin, CRP, haptoglobin ß, and surfactant protein A (isoform number 5) were all significantly higher in the OP pattern than in the UIP pattern. Gelsolin was cleaved into two fragments, a C-terminal half and N-terminal half, and the levels of both were significantly higher in the UIP pattern than in the OP pattern. CONCLUSIONS: Fragmented gelsolins may be associated with the pathogenesis of fibrosis in RA-ILD.

The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis.

BACKGROUND: It is believed that Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are useful biomarkers for the diagnosis of various types of interstitial lung diseases, including hypersensitivity pneumonitis (HP). The clinical features of chronic HP are similar to those of idiopathic interstitial pneumonias, especially idiopathic pulmonary fibrosis (IPF). OBJECTIVE: We sought to clarify the usefulness of serum KL-6 and SP-D for the diagnosis and management of chronic HP. METHODS: We examined serum KL-6 and SP-D levels and retrospectively evaluated the clinical parameters of acute HP (n = 35), chronic HP (n = 57), IPF (n = 54), collagen vascular disease-associated interstitial pneumonia (CVD-IP) (n = 67), and sarcoidosis (n = 47). We analyzed the relations between the two biomarkers and clinical data in chronic HP. RESULTS: Serum KL-6 and SP-D levels in acute HP (2710 U/ml and 338 ng/ml, median) and chronic HP (1500 U/ml and 264 ng/ml, median) were significantly higher than in IPF, CVD-IP, and sarcoidosis. The area under the curve (AUC) values for serum KL-6 and SP-D between chronic HP and IPF were 0.771 and 0.729, respectively. Serum KL-6 levels in chronic HP were significantly higher during episodes of acute exacerbation than 1 month before acute exacerbation. The serum KL-6 levels had correlations with serum SP-D and the percentage of lymphocytes in bronchoalveolar lavage fluid. CONCLUSIONS: Serum KL-6 and SP-D levels are useful for the diagnosis and management of chronic HP.

Antigen avoidance tests for diagnosis of chronic hypersensitivity pneumonitis.

BACKGROUND: Chronic hypersensitivity pneumonitis (HP) is induced by the inhalation of specific antigens. Patients with chronic HP may be able to improve their prognosis by avoiding these antigens. Chronic HP is often difficult to distinguish from idiopathic interstitial pneumonias (IIPs). OBJECTIVE: This study was performed to find out how antigen avoidance tests contribute to the diagnosis of chronic HP. METHODS: A retrospective analysis was conducted on 265 patients who underwent 2-week antigen avoidance tests between April 2002 and March 2012. The patients were classified into the following categories: acute HP, chronic HP, collagen vascular disease-associated interstitial pneumonia (CVD-IP), lung dominant connective tissue disease (LD-CTD), and IIPs. The following seven clinical parameters were evaluated: vital capacity, alveolar-arterial oxygen pressure difference, Krebs von den Lungen-6, surfactant protein-D, white blood cell count, C-reactive protein, and body temperature. These parameters were compared between the chronic HP group and a control group consisting of CVD-IP, LD-CTD, and IIPs. RESULTS: One-hundred and ninety-six patients with chronic HP and 43 control subjects were evaluated. All clinical parameters improved significantly in the chronic HP group but showed no significant changes in the control group. Four of the parameters changed significantly compared with the control group. Diagnostic criteria established using these data had a sensitivity of 51.0% and a specificity of 80.7%. CONCLUSIONS: It was difficult to diagnose chronic HP based solely on 2-week antigen avoidance tests; however, improved clinical parameters among patients supported the diagnosis of HP.

Validation of inhalation provocation test in chronic bird-related hypersensitivity pneumonitis and new prediction score.

RATIONALE: Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease induced by the inhalation of any of a wide variety of antigens. For example, bird-related HP (BRHP) results from the inhalation of avian antigens. The clinical features of chronic HP, including imaging and histological findings, are similar to those of idiopathic pulmonary fibrosis. Despite its status as the "gold standard," the inhalation provocation test (IPT) is rarely performed, because the methods and the criteria are not standardized. In 2000, we reported the utility of IPT for pigeon dropping extracts. OBJECTIVES: The purpose of the current study was to validate the utility and safety of the test, and to differentiate chronic HP from other interstitial lung diseases. METHODS: A total of 28 patients with chronic BRHP and 19 control subjects were evaluated in this retrospective study. We validated the previous criteria and proposed new criteria using prediction scores. MEASUREMENTS AND MAIN RESULTS: In the IPT using pigeon dropping extracts, the previous criteria showed a sensitivity of 78.6% and a specificity of 94.7% in this retrospective study. The increases in the peripheral white blood cell count and C-reactive protein levels are good indicators of a positive response to the inhalation challenge. We propose the use of the IPT prediction score (∆WBC [%] + 2 × ∆P[a - a]O2 [mm Hg], where WBC is white blood cell) and the prediction rule, which showed high sensitivity and specificity values of 92.9 and 94.7%, respectively. Two (1.5%) out of a total of 130 subjects who underwent the tests required treatment after the challenge. CONCLUSIONS: The IPT is a useful and safe tool for the diagnosis of chronic HP. The IPT prediction score that we have proposed has high sensitivity and specificity in the diagnosis of chronic BRHP.

Utility of immunological tests for bird-related hypersensitivity pneumonitis.

BACKGROUND: The reaction of specific antibodies and sensitized lymphocytes to antigens is important in hypersensitivity pneumonitis (HP). However, there are no known studies evaluating the utility of the lymphocyte proliferation test (LPT) or specific antibodies to avian antigens in diagnosing bird-related HP. In this study, we examined the sensitivity and specificity of these two tests. METHODS: Patients with acute bird-related HP (n=10), chronic bird-related HP (n=35), acute summer-type HP (n=14), and other interstitial pneumonia (IP) (n=76) were evaluated. The optimal cutoff values were determined by receiver operating curve (ROC) analyses of specific antibodies in serum and bronchoalveolar lavage fluid (BALF), and by conducting the LPT on mononuclear cells in peripheral blood and BALF. RESULTS: The sensitivity and specificity of the antibodies were 80-100% and 92-100% in acute bird-related HP, and 26-79% and 73-93% in chronic bird-related HP, respectively. The sensitivity and specificity of the LPT were 50-100% and 100% in acute bird-related HP, and 46% and 91% in chronic bird-related HP, respectively. CONCLUSIONS: Specific antibodies and the LPT are quite useful for diagnosing acute bird-related HP. The presence of specific antibodies in BALF and the results of LPT with peripheral blood mononuclear cells are particularly useful for diagnosing chronic bird-related HP.

Amyopathic dermatomyositis complicated with eosinophilic pneumonia.

A 67-year-old woman was admitted to our hospital due to dyspnea on exertion with lung abnormal shadows. A transbronchial lung biopsy specimen demonstrated eosinophilic pneumonia (EP). The patient also exhibited heliotrope eyelids without muscle weakness, which led to a diagnosis of amyopathic dermatomyositis (ADM). As we were unable to find any other causes of EP, we diagnosed her as having EP associated with ADM. Dermatomyositis (DM) has been reported to be associated with various interstitial lung diseases; however, only one case of EP associated with DM has been reported. We herein report the first case of EP complicated with ADM.

Airway arginase expression and Nω-hydroxy-nor-arginine effect on methacholine-induced bronchoconstriction differentiate Lewis and Fischer rat strains.

Innate airway hyperresponsiveness (AHR) is well modeled by two strains of rat, the hyperresponsive Fischer 344 rat and the normoresponsive Lewis rat. Arginase has been implicated in AHR associated with allergic asthma models. We addressed the role of arginase in innate AHR using the Fischer-Lewis model. In vivo arginase inhibition with N(ω)-hydroxy-nor-arginine (nor-NOHA) was evaluated on methacholine-induced bronchoconstriction in the Fischer and the Lewis rats. Arginase activity and mRNA expression were quantified in structural and resident cells of the proximal airway tree. The effect of nor-NOHA was evaluated on cultured tracheal smooth muscle proliferation. Fischer rats exhibited significantly greater changes in respiratory resistance and elastance in response to methacholine compared with Lewis rats. nor-NOHA reduced the methacholine-induced bronchoconstriction in the central airways of Lewis rats, while it did not change the innate AHR of Fischer rats. Lewis rats exhibited greater arginase activity in tracheal smooth muscle but a lower proliferation rate compared with Fischer rats. Smooth muscle proliferation was not affected by nor-NOHA in either strain of rats. The strain-specific arginase expression in the smooth muscle may contribute to the differences in sensitivity of the methacholine challenged airways of Lewis and Fischer rats to inhibition of arginase.

Penicilliosis marneffei complicated with interstitial pneumonia.

A 71-year-old man with interstitial pneumonia was hospitalized due to a pulmonary infection. He had been living in Thailand and had returned to Japan three months earlier. Antibiotic therapy initially cleared the infection; however, the patient's condition relapsed. Pseudomonas aeruginosa and Penicillium sp. were both detected in sputum and bronchial lavage fluid cultures and Penicillium sp. was identified to be P. marneffei. The infiltration observed on chest radiographs improved following treatment with itraconazole and tazobactam/piperacillin, and no relapse occurred. We herein report the first case of a non-HIV patient with P. marneffei infection in Japan.

Serodiagnosis of Mycobacterium avium complex pulmonary disease in rheumatoid arthritis.

BACKGROUND: Mycobacterium avium complex (MAC) pulmonary disease (PD) is often difficult and complicated to diagnose or to discriminate from follicular bronchitis, bronchiectasis, or other conditions associated with rheumatoid arthritis (RA) lung in the clinical setting. OBJECTIVE: We investigated whether a serologic test for anti-glycopeptidolipid (GPL) antibody was useful for distinguishing MAC-PD from RA lung in diagnosis. METHODS: Serum IgA antibody to MAC-specific GPL core antigen was measured by an enzyme immunoassay. Antibody levels were measured in sera from 14 RA patients with MAC-PD (RA + MAC), 20 RA patients with bronchial or bronchiolar lesions without MAC-PD (RA w/o MAC), 20 RA patients without pulmonary lesions (RA only), and 25 healthy volunteers (HV). RESULTS: The levels of serum anti-GPL antibodies were higher in the RA + MAC group than in the RA w/o MAC, RA-only, and HV groups (2.87 ± 2.83 vs. 0.50 ± 0.45, 0.31 ± 0.24, and 0.38 ± 0.10 U/ml, respectively; p < 0.001). With the cutoff point in receiver-operating characteristic analysis set at 0.7 U/ml, the serologic test differentiated RA + MAC from RA w/o MAC with a sensitivity of 100% and specificity of 90%. CONCLUSIONS: This serologic test for anti-GPL antibody is useful for diagnosing MAC-PD in RA.

Glycosyltransferases and glycosaminoglycans in bleomycin and transforming growth factor-ß1-induced pulmonary fibrosis.

Glycosaminoglycan (GAG) chains of proteoglycans (PGs) play important roles in fibrosis through cell-matrix interactions and growth factor binding in the extracellular matrix. We investigated the expression and regulation of PG core protein (versican) and key enzymes (xylosyltransferase [XT]-I, ß1,3-glucuronosyltransferase [GlcAT]-I, chondroitin-4-sulfotransferase [C4ST]) implicated in synthesis and sulfation of GAGs in bleomycin (BLM) and adenovirus-transforming growth factor (TGF)-ß1-induced lung fibrosis in rats. We also studied the role of GlcAT-I or TGF-ß1 and the signaling pathways regulating PG-GAG production in primary lung fibroblasts isolated from saline- or BLM-instilled rats. The mRNA for XT-I, GlcAT-I, C4ST, and versican was increased in the lung 14 days after BLM injury. In vitro studies indicate that fibrotic lung fibroblasts (FLFs) expressed more XT-I, C4ST, and chondroitin sulfate (CS)-GAGs than did normal lung fibroblasts at baseline. TGF-ß1 enhanced the expression of XT-I, C4ST-I, and versican in normal lung fibroblasts, whereas SB203580 or SB431542, by targeting p38 mitogen-activated protein kinase or TGF-ß type-1 receptor/activin receptor-like kinase 5, respectively, attenuated the response to both TGF-ß1 and FLFs on PG-GAG expression. Neutralizing anti-TGF-ß1 antibody abrogated FLF-conditioned medium-stimulated expression of XT-I, GlcAT-I, versican, and CS-GAG. Forced expression of TGF-ß1 in vivo enhanced versican, XT-I, GlcAT-I, and C4ST-I expression and PG-GAG deposition in rat lungs. Finally, induced expression of GlcAT-I gene in rat lung fibroblasts increased GAG synthesis by these cells. Together, our results provide new insights into the basis for increased PG-GAG deposition in lung fibrosis; inhibition of TGF-ß1-mediated or fibrosis-induced PG-GAG production by activin receptor-like kinase 5/p38 inhibitors may contribute to antifibrotic activity.

Rifampicin-induced acute kidney injury during the initial treatment for pulmonary tuberculosis: a case report and literature review.

A 47-year-old man diagnosed with pulmonary tuberculosis was referred to our hospital. Rifampicin, isoniazid, pyrazinamide and ethambutol were administered, and the patient's symptoms promptly improved. On the 19th hospital day, he developed acute kidney injury with a fever and chills. Renal biopsy specimens indicated tubulointerstitial nephritis. Suspecting rifampicin-induced acute kidney injury, we discontinued the rifampicin and administered levofloxacin in its place. The patient's serum creatinine level subsequently gradually improved. We herein report this case and review eight cases reported in Japan. We found that the rifampicin toxicity appeared at both the initial administration and readministration. All eight patients presented with proteinuria.

T cell-induced airway smooth muscle cell proliferation via the epidermal growth factor receptor.

Allergic asthma is a heterogeneous disease with no curative therapies. T cells infiltrate the airway smooth muscle (ASM) layer and may be implicated in airway remodeling and the increase of ASM mass, a cardinal feature of asthma. The mechanism by which CD4(+) T cells drive airway remodeling remains unknown. This study sought to determine the T cell-mediated mechanism of ASM cell proliferation. We hypothesized that CD4(+) T cells adhere to ASM cells via CD44, and induce ASM cell proliferation through the activation of the epidermal growth factor receptor (EGFR). A coculture model showed that the contact of antigen-stimulated CD4(+) T cells with ASM cells induced high levels of EGFR ligand expression in CD4(+) T cells and the activation of matrix metalloproteinase (MMP)-9, required for the shedding of EGFR ligands. The inhibition of EGFR and MMP-9 prevented the increase of ASM cell proliferation after coculture. The hyaluronan receptor CD44 is the dominant mediator of the tight adherence of T cells to ASM and is colocalized with MMP-9 on the cell surface. Moreover, the neutralization of CD44 prevents ASM cell hyperplasia. These data provide a novel mechanism by which antigen-stimulated CD4(+) T cells induce the remodeling indicative of a direct trophic role for CD4(+) T cells.

ICOS-expressing CD4 T cells induced via TLR4 in the nasal mucosa are capable of inhibiting experimental allergic asthma.

Modulation of adaptive immune responses via the innate immune pattern recognition receptors, such as the TLRs, is an emerging strategy for vaccine development. We investigated whether nasal rather than intrapulmonary application of Protollin, a mucosal adjuvant composed of TLR2 and TLR4 ligands, is sufficient to elicit protection against murine allergic lower airway disease. Wild-type, Tlr2(-/-), or Tlr4(-/-) BALB/c mice were sensitized to a birch pollen allergen extract (BPEx), then received either intranasal or intrapulmonary administrations of Protollin or Protollin admixed with BPEx, followed by consecutive daily BPEx challenges. Nasal application of Protollin or Protollin admixed with BPEx was sufficient to inhibit allergic lower airway disease with minimal collateral lung inflammation. Inhibition was dependent on TLR4 and was associated with the induction of ICOS in cells of the nasal mucosa and on both CD4+Foxp3+ and CD4+Foxp3- T cells of the draining lymph nodes (LNs), as well as their recruitment to the lungs. Adoptive transfer of cervical LN CD4+ICOS+, but not CD4+ICOS-, cells inhibited BPEx-induced airway hyperresponsiveness and bronchoalveolar lavage eosinophilia. Thus, our data indicate that expansion of resident ICOS-expressing CD4+ T cells of the cervical LNs by nasal mucosal TLR4 stimulation may inhibit the development of allergic lower airway disease in mice.

The presence of LPS in OVA inhalations affects airway inflammation and AHR but not remodeling in a rodent model of asthma.

Ovalbumin (OVA) is the most frequently used allergen in animal models of asthma. Lipopolysaccharide (LPS) contaminating commercial OVA may modulate the evoked airway inflammatory response to OVA. However, the effect of LPS in OVA on airway remodeling, especially airway smooth muscle (ASM) has not been evaluated. We hypothesized that LPS in commercial OVA may enhance allergen-induced airway inflammation and remodeling. Brown Norway rats were sensitized with OVA on day 0. PBS, OVA, or endotoxin-free OVA (Ef-OVA) was instilled intratracheally on days 14, 19, 24. Bronchoalveolar lavage (BAL) fluid, lung, and intrathoracic lymph node tissues were collected 48 h after the last challenge. Immunohistochemistry for α-smooth muscle actin, Periodic-Acid-Schiff staining, and real-time qPCR were performed. Airway hyperresponsiveness (AHR) was also measured. BAL fluid macrophages, eosinophils, neutrophils, and lymphocytes were increased in OVA-challenged animals, and macrophages and neutrophils were significantly lower in Ef-OVA-challenged animals. The ASM area in larger airways was significantly increased in both OVA and Ef-OVA compared with PBS-challenged animals. The mRNA expression of IFN-γ and IL-13 in lung tissues and IL-4 in lymph nodes was significantly increased by both OVA and Ef-OVA compared with PBS and were not significantly different between OVA and Ef-OVA. Monocyte chemoattractant protein (MCP)-1 in BAL fluid and AHR were significantly increased in OVA but not in Ef-OVA. LPS contamination in OVA contributes to the influx of macrophages and MCP-1 increase in the airways and to AHR after OVA challenges but does not affect OVA-induced Th1 and Th2 cytokine expression, goblet cell hyperplasia, and ASM remodeling.