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.

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.

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.

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.

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.

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.

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.

Treatment with a sphingosine-1-phosphate analog inhibits airway remodeling following repeated allergen exposure.

Sphingosine-1-phosphate (S1P) is an immunomodulatory lipid mediator that plays an important role in lymphocyte trafficking. Elevated levels of S1P are found in bronchoalveolar lavage (BAL) fluid of patients with asthma; however, its role in disease is not known. FTY720, a synthetic analog of S1P, has been shown to abrogate allergic inflammation and airway hyperresponsiveness following acute allergen challenge. However, its effects on asthmatic airway remodeling induced by repeated allergen exposure are unknown. Ovalbumin (OVA)-sensitized rats were challenged on days 14, 19, and 24 after sensitization. FTY720 or vehicle (PBS) therapy was administered 1 h prior to each challenge. BAL fluid and quantitative histological analysis were performed 48 h after the last challenge. FTY720 inhibited OVA-induced features of airway remodeling including increased airway smooth muscle mass and bronchial neovascularization, without affecting lymphocyte numbers in secondary lymphoid organs. Furthermore, CD3+ cells adjacent to airway smooth muscle bundles were increased in OVA-challenged rats but the increase was inhibited by FTY720. There was an expansion of bronchus-associated lymphoid tissue following FTY720 treatment of OVA-challenged animals. Real-time quantitative PCR revealed that Th2-associated transcription factors were inhibited following FTY720 therapy. Airway remodeling is a cardinal feature of severe asthma. These results demonstrate that allergen-driven airway remodeling can be inhibited by FTY720, offering potential new therapies for the treatment of severe asthma.

Synthetic double-stranded RNA enhances airway inflammation and remodelling in a rat model of asthma.

Respiratory viral infections are frequently associated with exacerbations of asthma. Double-stranded RNA (dsRNA) produced during viral infections may be one of the stimuli for exacerbation. We aimed to assess the potential effect of dsRNA on certain aspects of chronic asthma through the administration of polyinosine-polycytidylic acid (poly I:C), synthetic dsRNA, to a rat model of asthma. Brown Norway rats were sensitized to ovalbumin and challenged three times to evoke airway remodelling. The effect of poly I:C on the ovalbumin-induced airway inflammation and structural changes was assessed from bronchoalveolar lavage fluid and histological findings. The expression of cytokines and chemokines was evaluated by real-time quantitative reverse transcription PCR and ELISA. Ovalbumin-challenged animals showed an increased number of total cells and eosinophils in bronchoalveolar lavage fluid compared with PBS-challenged controls. Ovalbumin-challenged animals treated with poly I:C showed an increased number of total cells and neutrophils in bronchoalveolar lavage fluid compared with those without poly I:C treatment. Ovalbumin-challenged animals showed goblet cell hyperplasia, increased airway smooth muscle mass, and proliferation of both airway epithelial cells and airway smooth muscle cells. Treatment with poly I:C enhanced these structural changes. Among the cytokines and chemokines examined, the expression of interleukins 12 and 17 and of transforming growth factor-ß(1) in ovalbumin-challenged animals treated with poly I:C was significantly increased compared with those of the other groups. Double-stranded RNA enhanced airway inflammation and remodelling in a rat model of bronchial asthma. These observations suggest that viral infections may promote airway remodelling.

EGF receptor activation during allergic sensitization affects IL-6-induced T-cell influx to airways in a rat model of asthma.

EGF receptor (EGFR) is involved in cell differentiation and proliferation in airways and may trigger cytokine production by T cells. We hypothesized that EGFR inhibition at the time of allergic sensitization may affect subsequent immune reactions. Brown Norway rats were sensitized with OVA, received the EGFR tyrosine kinase inhibitor, AG1478 from days 0 to 7 and OVA challenge on day 14. OVA-specific IgE in serum and cytokines and chemokines in BAL were measured 24 h after challenge. To evaluate effects on airway hyperresponsiveness (AHR), rats were sensitized, treated with AG1478, intranasally challenged, and then AHR was assessed. Furthermore chemotactic activity of BALF for CD4(+) T cells was examined. The eosinophils, neutrophils and lymphocytes in BAL were increased by OVA and only the lymphocytes were reduced by AG1478. OVA significantly enhanced IL-6 concentration in BAL, which was inhibited by AG1478. However AHR, OVA-specific IgE and IL-4 mRNA expression in CD4(+) T cells were not affected by AG1478. BALF from OVA-sensitized/challenged rats induced CD4(+) T-cell migration, which was inhibited by both AG1478 treatment in vivo and neutralization of IL-6 in vitro. EGFR activation during sensitization may affect the subsequent influx of CD4(+) T cells to airways, mainly mediated through IL-6.

LTD4 induces HB-EGF-dependent CXCL8 release through EGFR activation in human bronchial epithelial cells.

Airway epithelial cells release proinflammatory mediators that may contribute to airway remodeling and leukocyte recruitment. We explored the hypothesis that leukotriene D4 (LTD4) may trigger the release of proremodeling factors through activation of the EGF receptor (EGFR). We particularly focused on the effects of LTD4 on release of heparin-binding EGF-like factor (HB-EGF) and IL-8 (CXCL8), a potent neutrophil chemoattractant that may be released downstream of EGFR activation. To address this hypothesis, both primary (NHBE) and transformed bronchial human epithelial cells (BEAS-2B) were grown on an air-liquid interface and stimulated with LTD4. HB-EGF and CXCL8 were evaluated by ELISA in cell culture supernatants. To explore the EGFR signaling pathway, we used a broad-spectrum matrix metalloproteinase (MMP) inhibitor, GM-6001, two selective EGFR tyrosine kinase inhibitors, AG-1478 and PD-153035, an HB-EGF neutralizing antibody, and a specific small interfering RNA (siRNA) against the EGFR. Expression of the CysLT1 cysteinyl leukotriene receptor was demonstrated by RT-PCR and immunocytochemistry in both BEAS-2B and NHBE cells. Four hours after stimulation with LTD4, HB-EGF and CXCL8 were significantly increased in cell culture supernatant. GM-6001 and montelukast, a specific CysLT1 receptor antagonist, blocked the LTD4-induced increase in HB-EGF. All inhibitors/antagonists decreased LTD4-induced CXCL8 release. siRNA against EGFR abrogated CXCL8 release following stimulation with LTD4 and exogenous HB-EGF. These findings suggest LTD4 induced EGFR transactivation through the release of HB-EGF in human bronchial epithelial cells with downstream release of CXCL8. These effects may contribute to epithelial-mediated airway remodeling in asthma and other conditions associated with cysteinyl leukotriene release.

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.

Depletion of CD8+ T cells enhances airway remodelling in a rodent model of asthma.

Airway remodelling is induced by persistent airway inflammation and may lead to severe asthma. T cells play a pivotal role in asthmatic airway inflammation but their role in remodelling is poorly understood. Although previous studies have revealed that CD8(+) T cells inhibit the late airway response and airway inflammation in a rat model of asthma, their effects on airway remodelling have not been evaluated. The aim of this study was to examine the role of CD8(+) T cells in airway remodelling. Brown Norway rats were sensitized with ovalbumin (OVA) on day 0. CD8(+) T cells in rats were depleted during the repeated challenges by treating them with a CD8alpha monoclonal antibody (OX-8). Control rats were treated with mouse ascites. Sensitized rats were challenged with OVA on days 14, 19 and 24 or were sham challenged with phosphate-buffered saline. On day 29, bronchoalveolar lavage and lung tissues were harvested. Repeated OVA inhalations evoked significant increases in the numbers of periodic acid-Schiff-positive epithelial cells and proliferating cell nuclear antigen-positive epithelial cells, and in airway smooth muscle mass compared to the control group. CD8-depleted rats had significant enhancement of these changes, principally affecting the large airways. These results suggest that endogenous CD8(+) T cells have inhibitory effects on airway remodelling in this model of asthma.

The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma.

The effects of remodeling of airway smooth muscle (SM) by hyperplasia on airway SM contractility in vivo are poorly explored. The aim of this study was to investigate the relationship between allergen-induced airway SM hyperplasia and its contractile phenotype. Brown Norway rats were sensitized with ovalbumin (OVA) or saline on day 0 and then either OVA-challenged once on day 14 and killed 24 h later or OVA-challenged 3 times (on days 14, 19, and 24) and killed 2 or 7 days later. Changes in SM mass, expression of total myosin, SM myosin heavy chain fast isoform (SM-B) and myosin light chain kinase (MLCK), tracheal contractions ex vivo, and airway responsiveness to methacholine (MCh) in vivo were assessed. One day after a single OVA challenge, the number of SM cells positive for PCNA was greater than for control animals, whereas the SM mass, contractile phenotype, and tracheal contractility were unchanged. Two days after three challenges, SM mass and PCNA immunoreactive cells were increased (3- and 10-fold, respectively; P < 0.05), but airway responsiveness to MCh was unaffected. Lower expression in total myosin, SM-B, and MLCK was observed at the mRNA level (P < 0.05), and total myosin and MLCK expression were lower at the protein level (P < 0.05) after normalization for SM mass. Normalized tracheal SM force generation was also significantly lower 2 days after repeated challenges (P < 0.05). Seven days after repeated challenges, features of remodeling were restored toward control levels. Allergen-induced hyperplasia of SM cells was associated with a loss of contractile phenotype, which was offset by the increase in mass.

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.

Elemental analysis of inorganic dusts in lung tissues of interstitial pneumonias.

People have the opportunity to inhale inorganic dusts under various environments. Inorganic dust exposures as a result of occupational exposure may induce or modulate pulmonary fibrosis. We analyzed the deposition of elements in lung tissues of patients with idiopathic pulmonary fibrosis (IPF) and compared element deposition with chronic hypersensitivity pneumonitis (chronic HP) and collagen vascular diseases (CVD). Thirty-five patients (18 men and 17 women with the mean age of 64.3) were studied, including 15 IPF, 8 chronic HP, 6 CVD, and 6 control patients. Four IPF patients have occupational dust exposures. Inorganic particles were counted by polarizing light microscopy and scanning electron microscopy. Energy dispersive X-ray spectroscopy was performed to analyze an elemental deposition. The number of birefringent particles was greater in IPF, even in IPF without occupational exposure, than in controls. The silicon (Si)/sulfur (S) ratio and aluminium (AI)/S ratio were increased in IPF independent of occupational exposure. A point elemental analysis showed that the major compound of the particles was aluminium-silicate in IPF. These results suggest that unrecognized dust exposures are relatively common in some IPF patients and aluminium-silicate could be associated with the disease process of IPF.

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.

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.