A RAS inhibitor reduces allergic airway remodeling via regulating IL-33-derived type 2 innate lymphoid cells.

Purpose: IL-33 is known to induce corticosteroid-resistant eosinophilic inflammation and airway remodeling by activating type 2 innate lymphoid cells (ILC2s). Although the RAS signal pathway plays an important role in IL-33-induced ILC2s activation and airway remodeling, it is not known if RAS inhibitors are effective against refractory asthma. We examined the effects of the RAS inhibitor XRP44X in refractory asthma. Methods: RAS activity were examined by BAL fluid and T-cells isolated from spleen cells in Dermatophagoides pteronyssinus (Dp)-sensitized/challenged acute allergic airway inflammation model. A chronic allergic airway inflammation mouse model was generated by challenged with Dp. XRP44X and/or fluticasone were administrated nasally to different experimental groups. The effects of nasal simultaneous administration of XRP44X or fluticasone were assessed in mice administrated with IL-33 or Dp. Results: RAS activity in CD4+ T cells stimulated by Dp were suppressed by XRP44X. Although fluticasone and XRP44X only improved allergic airway inflammation in mice, XRP44X in combination with fluticasone produced further improvement in not only eosinophilic inflammation but also bronchial subepithelial thickness. XRP44X suppressed IL-5 and IL-13 production from ILC2s, although this effect was not suppressed by fluticasone. IL-33-induced airway inflammation resistant to fluticasone was ameliorated by XRP44X via regulating the accumulation of lung ILC2s. Conclusion: The RAS signal pathway plays a crucial role in allergen-induced airway remodeling associated with ILC2s. XRP44X may have therapeutic potential for refractory asthma.

Lysophosphatidic Acid Regulates the Differentiation of Th2 Cells and Its Antagonist Suppresses Allergic Airway Inflammation.

BACKGROUND: Lysophosphatidic acid (LPA), a prototypic member of a large family of lysophospholipids, has been recently shown to play a role in immune responses to respiratory diseases. The involvement of LPA in allergic airway inflammation has been reported, but the mechanism remains unclear. OBJECT: We analyzed the biological activity of LPA in vitro and in vivo and investigated its role in allergic inflammation in mice using an LPA receptor 2 (LPA2) antagonist. METHODS: We used a murine model with acute allergic inflammation, in which mice are sensitized and challenged with house dust mite, and analyzed airway hyperresponsiveness (AHR), pathological findings, Th2 cytokines, and IL-33 in bronchoalveolar lavage fluid (BALF) and lung homogenates. The effect of LPA on Th2 differentiation and cytokine production was examined in vitro using naive CD4+ T cells isolated from splenocytes. We also investigated in vivo the effects of LPA on intranasal administration in mice. RESULTS: The LPA2 antagonist suppressed the increase of AHR, the number of total cells, and eosinophils in BALF and lung tissue. It also decreased the production of IL-13 in BALF and IL-33 and CCL2 in the lung. LPA promoted Th2 cell differentiation and IL-13 production by Th2 cells in vitro. Nasal administration of LPA significantly increased the number of total cells and IL-13 in BALF via regulating the production of IL-33 and CCL-2-derived infiltrating macrophages. CONCLUSION: These findings suggest that LPA plays an important role in allergic airway inflammation and that the blockade of LPA2 might have therapeutic potential for bronchial asthma.

A Long-term Survival Case of Pulmonary Tumor Thrombotic Microangiopathy due to Gastric Cancer Confirmed by the Early Diagnosis based on a Transbronchial Lung Biopsy.

Pulmonary tumor thrombotic microangiopathy (PTTM) is an acute, progressive, and fatal disease. PTTM manifests as subacute respiratory failure with pulmonary hypertension, progressive right-sided heart failure, and sudden death. An antemortem diagnosis of PTTM is very difficult to obtain, and many patients die within several weeks. We herein report a case of PTTM diagnosed based on a transbronchial lung biopsy. In this case, we finally diagnosed PTTM due to gastric cancer because of its histological identity. The patient was administered chemotherapy, including angiogenesis inhibitors, against gastric cancer at an early age and survived for a long time.

A Tuberculous Bronchial Artery Aneurysm with Abnormal Findings on Autofluorescence Imaging Bronchoscopy.

Pulmonary tuberculosis is a common disease that may result in hemoptysis. Fetal hemoptysis is known to be related to the rupture of a pulmonary aneurysm formed in the cavity wall. We herein report a case of non-cavity pulmonary tuberculosis that developed with massive hemoptysis following bronchial artery aneurysm. Bronchial artery embolization was performed, and autofluorescence imaging bronchoscopy was conducted one month after the anti-tuberculosis treatment. Bright-green color was observed in the ulcerative lesion with a white coat, corresponding to the bronchial artery aneurysm. This is the first report of the autofluorescence imaging observation of an ulcerative lesion caused by bronchial tuberculosis.

[PARADOXICAL RESPONSE DURING TREATMENT OF PULMONARY TUBERCULOSIS].

BACKGROUND: Paradoxical response (PR) is defined as a clinical or radiological worsening in patients receiving adequate anti-tuberculosis treatment, with the exclusion of documented relapse or of other disease presentations. Although most patients with PR show spontaneous improvement, some cases presenting with diffuse alveolar damage have also been reported. METHODS: Retrospective clinical and laboratory data were collected on 89 patients of pulmonary tuberculosis who were treated at our hospital between April 2013 and January 2019. RESULTS: PR occurred in 21 patients (24%), and the median onset time after anti-tuberculosis treatment was 22 days. The time to onset of PR was shorter in diffuse pulmonary infiltrates group than in local pulmonary infiltrates group or in pleural effusion group. Low serum albumin, elevated lactate dehydrogenase (LDH), high Creactive protein (CRP) and chest radiographic appearance exceeding one-lung area were associated with PR incidence. There was no difference in sputum smear grading and pulmonary cavitation. Six out of the ten patients died, developing PR with diffuse pulmonary infiltrates. CONCLUSION: Low albumin and chest radiographic appearance exceeding one-lung area were risk factors for developing PR. Diffuse pulmonary infiltrates in early phase of anti-tuberculosis treatment was related with Inhospital mortality.

The clinical features of older patients with lung cancer in comparison with their younger counterparts.

BACKGROUND: Older patients with lung cancer have increased over the past decades. Several standard treatments for older patients were established, but their clinical features in real world clinics remain unknown. Thus, we performed a retrospective study to clarify the clinical features of them. METHODS: The patients with lung cancer who were admitted to our hospital between April 1, 2012 and March 31, 2015 were retrospectively analyzed. Patients older than 75 years were defined as older patients. Standard treatments were based on the guidelines. RESULTS: In total, 333 patients were analyzed. The older patients had a poor performance status (PS), more comorbidities, and fewer opportunities to receive standard treatments. The prognosis of the older patients who received standard treatments was superior to that of those who did not. The therapeutic efficacy of standard treatments for older patients with stages I and II diseases was similar to their younger counterparts. However, the prognosis of older patients with advanced stage, especially stage III disease, was poor. The tolerability of first-line chemotherapy by older patients was comparable with their younger counterparts, but the older patients had fewer opportunities to receive several chemotherapy regimens, even second line chemotherapy. CONCLUSIONS: We should positively consider standard treatments for older patients. However, not only their shorter life expectancy but also their poor PS and multiple comorbidities that sometimes render patients unable to receive standard treatments and several chemotherapy regimens, make their prognosis poor. The standard treatments for older patients, especially in locally advanced stages, require modification.

Neutrophils induce smooth muscle hyperplasia via neutrophil elastase-induced FGF-2 in a mouse model of asthma with mixed inflammation.

BACKGROUND: Bronchial asthma is traditionally characterized by chronic allergic inflammation, including eosinophilia and elevated Th2 cytokines. Recently, IL-17-derived neutrophil infiltration was shown to correlate with asthma severity and airway remodelling. OBJECTIVE: To investigate the role of IL-17-derived neutrophils in airway remodelling in chronic bronchial asthma. METHODS: We utilized house dust mite antigen-induced mouse models of asthma. Intranasal sensitization and chronic antigen challenge caused a mixed allergic inflammation that included eosinophils and neutrophils (Mix-in group). We neutralized IL-17 and fibroblast growth factor (FGF-2) and investigated the mechanism of airway remodelling in the Mix-in group. RESULTS: The Mix-in group displayed neutrophilic infiltration and high levels of IL-17 in lung tissue. The Mix-in group also exhibited more bronchial smooth muscle hyperplasia. IL-17 neutralization decreased the magnitude of all of these effects in the Mix-in group. Antibody arrays revealed an increase in FGF-2 in the Mix-in Group relative to the Eo-ip group, and FGF-2 elevation was associated with smooth muscle hypertrophy/hyperplasia. High concentrations of neutrophil elastase enhanced E-cadherin/ß-catenin signalling in bronchial epithelial cells. Neutrophil elastase inhibitor treatment decreased FGF-2 production and E-cadherin/ß-catenin signalling, which inhibited smooth muscle hyperplasia. CONCLUSION: The IL-17/neutrophil axis may play an important role in airway remodelling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation and accordingly represents an attractive therapeutic target for severe asthma.

Analysis of acute exacerbation of interstitial lung disease associated with chemotherapy in patients with lung cancer: A feasibility of S-1.

BACKGROUND: Interstitial lung disease (ILD) is commonly concomitant with lung cancer, and its acute exacerbation (AE) is the most serious complication in patients receiving treatment for lung cancer. METHODS: To investigate the incidence and characteristic features of AE of ILD, we conducted a retrospective study of 665 consecutive patients with lung cancer who were treated at our institute between 2008 and 2014. RESULTS: Among the 665 patients, 74 (11.1%) had preexisting ILD, and 64 of them received chemotherapy. Four of the 64 patients (6.3%) had experienced AE of ILD, and two (3.1%) died of respiratory failure during first-line chemotherapy. The use of a combination of carboplatin with tegafur-gimeracil-oteracil potassium (S-1) or paclitaxel as a first-line chemotherapy for non-small cell lung cancer led to a lower frequency of AE, at 8.3% (1/12) and 9.1% (1/11), respectively. The incidence of AE rose to 12.8% (5/39) during second-line treatment, and 14 (total: 15 times) of the 64 patients (21.9%) experienced AE from the time of diagnosis to the end of treatment. The incidence of AE was 17.7% (6/34), 15.8% (3/19), 5.0% (2/40), and 4.2% (1/24) in the paclitaxel-, vinorelbine-, etoposide-, and S-1-containing regimens, respectively. No difference in clinical features and laboratory data was detected between the AE and non-AE groups. CONCLUSIONS: Although this was a small retrospective study, its findings showed that S-1 and etoposide may be relatively safe options for the treatment of patients with lung cancer and concomitant ILD.

An analysis of the clinical features of lung cancer in patients with connective tissue diseases.

BACKGROUND: Patients with connective tissue diseases (CTDs) are at increased risk for lung cancer (LC); interstitial lung disease (ILD) is a common form of organ dysfunction in cases of CTD. However, the influence of ILD on the treatment and prognosis in LC patients with CTD is unclear. METHODS: Between January 2010 and December 2014, 27 patients among all patients with CTD at our institution were diagnosed with primary LC. We retrospectively analyzed the clinical features, treatment modalities, and outcomes of these patients, and evaluated the potential prognostic factors. Forty-four LC patients without CTD were also analyzed as a control cohort. RESULTS: LC patients with CTD had a significantly higher incidence of ILD as a complication compared with those without CTD (52% and 14%, respectively). CTD-associated ILD (CTD-ILD) at diagnosis was associated with significantly worse survival in LC patients with CTD. Multivariate analysis demonstrated that the complication of CTD-ILD was an independent poor prognostic factor in LC patients with CTD. The incidence of acute exacerbation (AE) of CTD-ILD was 21% among LC patients with CTD, and all of these patients died despite intensive treatment including high-dose corticosteroids. The restrictions in curative therapy for LC due to the presence of ILD and AE of CTD-ILD were thought to be the major reasons for the poor outcome. CONCLUSIONS: LC patients with CTD had a high prevalence of ILD, and the presence of CTD-ILD was significantly associated with poor prognosis.

An Autopsy Case of Aortic Intimal Sarcoma Initially Diagnosed as Polyarteritis Nodosa.

A 61-year-old man had hypertension with stenosis in the left renal artery. When his fever, abdominal pain, and renal dysfunction progressed, he was admitted to our hospital. He was diagnosed with polyarthritis nodosa. His renal function rapidly deteriorated despite immunosuppressive therapy. His digestive tract perforated twice, and he subsequently died. An autopsy revealed that aortic intimal sarcoma caused stenosis in multiple arteries. Both polyarteritis nodosa and aortic intimal sarcoma are very rare diseases and the diagnoses are very difficult. It is very important to consider these entities when making a differential diagnosis of vasculitis.

Analysis of the Prognostic Factors of Extensive Disease Small-Cell Lung Cancer Patients in Tokushima University Hospital.

BACKGROUND: Small-cell lung cancer (SCLC) presents aggressive clinical behavior, and its prognosis is still poor. Previously, performance status (PS), or the existence of brain, bone, or liver metastasis were reported to be unfavorable prognostic factors. Given the recent progress of treatment modalities such as radiotherapy techniques and bone modifying agents, the prognostic factors might be different from previous findings. Therefore, we analyzed the prognostic factors of extensive disease SCLC (ED-SCLC) in recent years. METHODS: ED-SCLC patients treated in Tokushima University Hospital between 2010 and 2016 were analyzed. Log-rank test and the Cox proportional hazards regression model was used in univariate and multivariate analysis, respectively. RESULTS: Totally, 79 patients were analyzed. In the univariate analysis, age, PS, interstitial pneumonia (IP), liver metastasis, pleural dissemination, neutrophil counts, hypoalbuminemia, hypercalcemia and several liver and biliary enzymes were identified as poor prognostic factors. In the multivariate analysis, age, PS, IP, and liver and biliary enzymes were identified. Moreover, the PS in patients with liver metastasis was significantly worsened. CONCLUSIONS: In this study, we newly demonstrated that IP was a significant poor prognostic factor of ED-SCLC. Although liver metastasis was not extracted in multivariate analysis, it may have an impact on the prognosis of ED-SCLC. J. Med. Invest. 63: 286-293, August, 2016.

Clinical features and outcome of acute exacerbation of interstitial pneumonia associated with connective tissue disease.

Acute exacerbation (AE) of interstitial lung disease is reported to be developed in not only idiopathic pulmonary fibrosis but also connective tissue disease-associated interstitial pneumonia (CTD-IP). As the significance of AE of CTD-IP has not been so widely recognized, its clinical feature is not fully elucidated. In the present study, we investigated the incidence, clinical features and outcome of AE of CTD-IP. We retrospectively reviewed admitted cases in our department with medical record from 2011 to 2015. Among 155 patients with CTD-IP, 10 (6.5%) cases developed AE (6 rheumatoid arthritis, 2 polymyositis/dermatomyositis, 1 systemic lupus erythematosus, 1 Sjögren syndrome), and one died of AE within 30 days. Median survival time after the onset of AE was 169 days in all 10 patients. The treatment with immunosuppressant just before AE onset might improve the prognosis of AE. The median survival time after the onset of AE was significantly longer in patients showing good response to corticosteroid compared with those with poor response to corticosteroid (805 days and 45 days, respectively) (p <0.05), suggesting that there are some cases in CTD-IP, showing the good response to corticosteroid even when AE was complicated. J. Med. Invest. 63: 294-299, August, 2016.

IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-ß, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

Targeted reduction of CCR4⁺ cells is sufficient to suppress allergic airway inflammation.

BACKGROUND: Bronchial asthma is characterized by allergic airway inflammation involving C-C chemokine receptor type 4 (CCR4)-positive Th2 cells. As such, we hypothesize that the disease can be alleviated by targeted-elimination of CCR4⁺ cells. Thymus and activation-regulated chemokine (TARC)-PE38, a TARC fused the exotoxin fragment PE38 from Pseudomonas aeruginosa, has been shown to efficiently kill CCR4⁺ cells by delivering the exotoxin fragment PE38 into CCR4⁺ cells. To test our hypothesis, we examined whether TARC-PE38 could suppress allergic airway inflammation in a mouse model of house dust mite (HDM)-induced allergic airway inflammation. METHODS: We evaluated the effect of TARC-PE38 on the major characteristics of HDM-induced allergic airway inflammation. Airway hyperresponsiveness, lung histopathology, lung Th1/Th2 cell populations, and concentrations of Th1/Th2 cytokines in the lungs were assessed in HDM-sensitized and challenged mice in the presence and absence of TARC-PE38. RESULTS: TARC-PE38 efficiently suppressed allergic airway inflammation by significantly reducing airway hyperresponsiveness, the overall area of inflammation, and goblet cell hyperplasia. In HDM-sensitized and challenged mice, TARC-PE38 specifically reduced the numbers of CCR4⁺ cells. This reduction was associated with a significant decrease in the production of Th2 cytokines in the airway,and a decrease in the number of leukocytes, including macrophages, eosinophils and lymphocytes, within the subepithelial area of the lungs and airway lumen. TARC-PE38 had noeffect on Th1 cells. CONCLUSION: Our data suggest that the elimination of CCR4⁺ cells via TARC-PE38 treatment is sufficient to control allergic airway inflammation and airway hyperresponsiveness.

Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats.

BACKGROUND: Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been reported to be associated with interstitial lung disorders, and their high incidence and mortality have become a matter of great concern, especially in Japan. In this study, we investigated the effect of gefitinib on different phases of radiation-induced lung disorders in an experimental model. METHODS: The thoraxes of Wistar rats were irradiated on day 1 with a single X-ray dose of 20 Gy, and gefitinib (50 mg/kg/day) was orally administered from day 1 to 14. The rat lungs were harvested on days 15 and 57 and the bronchoalveolar lavage (BAL) was performed. RESULTS: Gefitinib treatment increased the infiltration of inflammatory cells, which produced more pro-inflammatory cytokines (IL-6, IL-1ß), in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57. CONCLUSIONS: In irradiated rats, gefitinib treatment augmented lung inflammation, including inflammatory cell infiltration and pro-inflammatory cytokine expression, while gefitinib treatment attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation.

Psychiatric symptoms in a patient with Churg-Strauss syndrome.

We report a case of Churg-Strauss syndrome (CSS) in a patient with multiple cerebral infarctions and psychotic symptoms. A 67-year-old man presented a high-grade fever and delirium. He was clinically diagnosed with Churg-Strauss syndrome on the basis of the presence of asthma, neuropathy, blood eosinophilia, and increased myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) activities. Though multiple cerebral infarctions are irreversible, this patient's psychiatric symptoms improved with steroid treatment. Psychiatric symptoms associated with CSS are very rare.

Investigation of the outpatient chemotherapy for lung cancer patients in Tokushima University Hospital.

Platinum-doublet regimens and docetaxel as first- and second-line chemotherapy, respectively, are shown to prolong the survival of lung cancer patients in various randomized phase III studies. However, the evidence for the efficacy of chemotherapy for lung cancer in the clinical practice is still insufficient. In the present study, we investigated the effectiveness and safety of outpatient chemotherapy for lung cancer in the clinical practice. Ninety-four lung cancer cases were retrospectively analyzed. Among these cases, 67 (71.3%) were non-small cell lung cancer (NSCLC) and 27 (28.7%) were small cell lung cancer (SCLC). The response rates in SCLC and NSCLC patients were 55.6% (15/27) and 16.9% (11/65), respectively. Objective tumor response rates for the patients were found to decrease substantially with each line of treatment as described previously. All adverse events were well tolerated and no treatment-related death was observed. Median time to treatment failures (TTFs) of first-line treatment were 10.1 months and 4.8 months in SCLC and NSCLC, respectively. These findings indicate that even in the setting of clinical practice, the efficacy and safety of chemotherapy is strictly insured by the appropriate therapeutic management.