Concurrent Double Fungal Infections of the Skin Caused by Phialemoniopsis endophytica and Exophiala jeanselmei in a Patient with Microscopic Polyangiitis.

is missing (Short communication).

A panel study of airborne particulate matter composition versus concentration: Potential for inflammatory response and impaired pulmonary function in children.

BACKGROUND: The relationship between airborne particulate matter (PM) and pulmonary function in children has not been consistent among studies, potentially owing to differences in the inflammatory response to PM, based on PM types and sources. The objective of this study was to investigate the effect of airborne PM on pulmonary function in schoolchildren and its potential for an inflammatory response. METHODS: Daily morning peak expiratory flow (PEF) was measured in 339 schoolchildren in February 2015. Interleukin (IL)-8 production was assessed in THP1 cells stimulated by airborne PM collected every day during the study period, and these IL-8 concentrations are described as the daily IL-8 levels. A linear mixed model was used to estimate the association between PEF values and the daily levels of suspended PM (SPM), PM diameters smaller than 2.5 µm (PM2.5), and IL-8. RESULTS: The daily IL-8 levels were significantly associated with those of SPM and PM2.5. A 0.83 µg/mL increase in IL-8 levels was significantly associated with a -1.07 L/min (95% confidence interval, -2.05 to -0.08) decrease in PEF. A 12.0 µg/m3 increase in SPM and a 10.0 µg/m3 increase in PM2.5 were associated with a -1.36 L/min (-2.93 to 0.22) and -1.72 L/min (-3.82 to 0.36) decreases in PEF, respectively. There were no significant relationships between PEF, SPM, and PM2.5. CONCLUSIONS: These findings suggest that the effects of airborne PM on pulmonary function in schoolchildren might depend more on the pro-inflammatory response than the mass concentration of the PM.

Association between pulmonary function and daily levels of sand dust particles assessed by light detection and ranging in schoolchildren in western Japan: A panel study.

BACKGROUND: An important aspect of sand dust emissions in association with respiratory disorders is the quantity of particulate matter. This is usually expressed as particulate matter less than 10 µm (PM10) and 2.5 µm (PM2.5). However, the composition of PM10 and PM2.5 varies. Light detection and ranging is used to monitor sand dust particles originating in East Asian deserts and distinguish them from air pollution aerosols. The objective of this study was to investigate the association between the daily levels of sand dust particles and pulmonary function in schoolchildren in western Japan. METHODS: In this panel study, the peak expiratory flow (PEF) of 399 schoolchildren was measured daily from April to May 2012. A linear mixed model was used to estimate the association of PEF with the daily levels of sand dust particles, suspended particulate matter (SPM), and PM2.5. RESULTS: There was no association between the daily level of sand dust particles and air pollution aerosols, while both sand dust particles and air pollution aerosols had a significant association with SPM and PM2.5. An increment of 0.018 km(-1) in sand dust particles was significantly associated with a decrease in PEF (-3.62 L/min; 95% confidence interval, -4.66 to -2.59). An increase of 14.0 µg/m(3) in SPM and 10.7 µg/m(3) in PM2.5 led to a significant decrease of -2.16 L/min (-2.88 to -1.43) and -2.58 L/min (-3.59 to -1.57), respectively, in PEF. CONCLUSIONS: These results suggest that exposure to sand dust emission may relate to pulmonary dysfunction in children in East Asia.

Effect of Asian dust on pulmonary function in adult asthma patients in western Japan: A panel study.

BACKGROUND: Asian dust (AD) has become a major health concern. The concentration of AD is typically expressed in particulate matter less than 10 µm (PM10) and 2.5 µm (PM2.5). However, PM10 and PM2.5 consist of various substances besides AD. Light detection and ranging (LIDAR) systems can selectively measure the quantity of AD particles to distinguish non-spherical airborne particles from spherical airborne particles. The objective of this study was to investigate the relationship between pulmonary function in adult asthma patients and AD using LIDAR data. METHODS: Subjects were 231 adult asthma patients who had their morning peak expiratory flow (PEF) measured from March to May 2012. A linear mixed model was used to estimate the association of PEF with sand dust particles detected by LIDAR. RESULTS: Increases in the interquartile range of AD particles (0.018 km(-1)) led to changes in PEF of -0.42 L/min (95% confidence interval [CI], -0.85 to 0.01). An increase of 11.8 µg/m(3) in suspended particulate matter and 6.9 µg/m(3) in PM2.5 led to decreases of -0.17 L/min (-0.53 to 0.21) and 0.03 L/min (-0.35 to 0.42), respectively. A heavy AD day was defined as a day with a level of AD particles >0.032 km(-1), which was the average plus one standard deviation during the study period, and six heavy AD days were identified. Change in PEF after a heavy AD day was -0.97 L/min (-1.90 to -0.04). CONCLUSIONS: Heavy exposure to AD particles was significantly associated with decreased pulmonary function in adult asthma patients.

γ-Tocotrienol reduces human airway smooth muscle cell proliferation and migration.

AIMS: Vitamin E is an antioxidant that occurs in 8 different forms (α, ß, γ, and δ tocopherol and tocotrienol). Clinical trials of tocopherol supplementation to assess the impact of antioxidant activity in asthma have yielded equivocal results. Tocotrienol exhibits greater antioxidant activity than tocopherol in several biological phenomena in vivo and in vitro. We tested the effect of tocotrienol on human airway smooth muscle (ASM) cell growth and migration, both of which mediate airway remodeling in asthma. MAIN METHODS: We measured platelet-derived growth factor-BB (PDGF-BB)-induced ASM cell proliferation and migration by colorimetric and Transwell migration assays in the presence and absence of γ-tocotrienol (an isoform of tocotrienol). KEY FINDINGS: PDGF-BB-induced ASM cell proliferation and migration were inhibited by γ-tocotrienol. This effect was associated with inhibition of RhoA activation, but it had no effect on p42/p44 mitogen-activated protein kinase (MAPK) or Akt1 activation. We confirmed that pharmacological inhibition of Rho kinase activity was sufficient to inhibit PDGF-BB-induced ASM cell proliferation and migration. SIGNIFICANCE: γ-Tocotrienol could impart therapeutic benefits for airway remodeling in asthma by inhibiting human ASM cell proliferation and migration.

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema.

Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2100 genes selected for cardiovascular diseases among 20 077 European-Americans and 6900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with per cent emphysema and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and per cent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10(-6)) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10(-7)). Both single-nucleotide polymorphisms (SNPs) flank the gene for apolipoprotein M (APOM), a component of high-density lipoprotein (HDL) cholesterol. Both were replicated in an independent cohort. SNPs in a second gene related to apolipoprotein M and HDL, PCSK9, were associated with FEV1/FVC ratio among African-Americans. rs707974 was associated with per cent emphysema among European-Americans and African-Americans and APOM expression was related to FEV1/FVC ratio and per cent emphysema. Higher HDL levels were associated with lower FEV1/FVC ratio and greater per cent emphysema. These findings suggest a novel role for the apolipoprotein M/HDL pathway in the pathogenesis of COPD and emphysema.

Effects on asthma and induction of interleukin-8 caused by Asian dust particles collected in western Japan.

OBJECTIVE: Asian dust storms (ADS) contain various airborne particles that may augment airway inflammation by increasing the level of interleukin-8. The objective of the study was to investigate the association of exposure to an ADS with worsening of symptoms of adult asthma and the effect of ADS particles on interleukin-8 transcriptional activity. METHODS: The subjects were 112 patients with mild to moderate asthma who recorded scores for their daily upper and lower respiratory tract symptoms and measured morning peak expiratory flow (PEF) from March to May 2011. Interleukin-8 transcriptional activity was assessed in THP-G8 cells that were exposed to airborne particles collected during days of ADS exposure. RESULTS: Of the 112 patients, 31 had comorbid allergic rhinitis (AR) and/or chronic sinusitis (CS), and had worsened scores for upper respiratory tract symptoms on ADS days compared to non-ADS days. Scores for lower respiratory tract symptoms during ADS days were higher than non-ADS days in all patients. Three patients also had unscheduled hospital visits for exacerbation of asthma on ADS days. However, there was no significant difference in daily morning PEF between ADS and non-ADS days. Airborne particles collected on ADS days induced interleukin-8 transcriptional activity in THP-G8 cells compared to the original soil of the ADS. CONCLUSION: Exposure to an ADS aggravates upper and lower tract respiratory symptoms in patients with adult asthma. ADS airborne particles may increase airway inflammation through enhancement of interleukin-8 transcriptional activity.

Diagnostic and prognostic impact of serum-soluble UL16-binding protein 2 in lung cancer patients.

UL16-binding protein 2 (ULBP2) is one of the ligands for NKG2D (NKG2DL). ULBP2 expression is induced in transformed cells and is recognized by immune effector cells via the activating NKG2D immunoreceptor. Soluble forms of NKG2DL have been reported in the serum of patients with several types of cancer. The present study investigated the diagnostic and prognostic significance of serum-soluble ULBP2 (sULBP2) in lung cancer patients. We used flow cytometry to evaluate the surface expression of NKG2DL by various lung cancer cells, while sULBP2 was measured using our original ELISA. In addition, the immunological effect of sULBP2 on peripheral blood mononuclear cells (PBMC) was examined by the (51) Cr release assay. We found that ULBP2 was highly expressed and that the sULBP2 level was elevated in supernatants of cultured non-small-cell lung cancer (NSCLC) cells as well as in the serum of NSCLC patients. ULBP2 levels were especially high in squamous cell carcinoma (SQ) patients. Clinical stage IIIB and IV NSCLC patients with a sULBP2 level ≥ 8.7 pg/mL showed significantly shorter survival than patients with sULBP2 <8.7 pg/mL. In multivariate analysis, a sULBP2 level ≥ 8.7 pg/mL (hazard ratio [HR], 2.13; P = 0.038) and clinical stage IV (HR, 2.65; P = 0.019) were independent determinants of a poor outcome. As a possible mechanism, we demonstrated that sULBP2 directly suppresses the cytolytic activity of PBMC. In conclusion, ULBP2 is the most significant NKG2DL for lung cancer, and sULBP2 is useful in the diagnosis of SQ and as a prognostic indicator for patients with advanced NSCLC.

Pollen augments the influence of desert dust on symptoms of adult asthma patients.

BACKGROUND: East Asian desert dust storms that occur during mainly spring are called Asian dust storms (ADS). Our objective was to study the association of pollen and ADS with symptoms of adult asthma patients in Japan. METHODS: We designed a telephone survey to investigate the upper and lower respiratory, ocular, and skin symptoms of asthma patients during ADS in February, March, and December on 2009. Peak expiratory flow (PEF) was also measured from February to May. RESULTS: We surveyed 106 patients in February, 101 patients in March, and 103 patients in December. In February and March, Japanese cedar and/or cypress pollen was also in the atmosphere during ADS, but no pollen was identified during December survey. Worsening of upper or lower respiratory, ocular, or skin symptoms was noted by 20.8% of patients in February, 33.7% in March, and 16.5% in December. Worsening of symptoms was significantly more common in March than in February or December. Two patients needed emergency treatment for exacerbation during ADS in March, but no patient needed hospitalization in any period. There was no significant difference of the daily morning PEF/personal best PEF ratio between ADS days and control days. However, in patients with worsening of upper and/or lower respiratory tract symptoms, the daily morning PEF/personal best ratio was significantly associated with the atmospheric level of particulate matter, but not with levels of pollen or other air pollutants. CONCLUSIONS: Pollen augmented symptoms in adult asthma patients, but ADS on its own also were able to aggravate symptoms and pulmonary function.

Correlation between Asian dust storms and worsening asthma in Western Japan.

BACKGROUND: Severe wind storms during spring in East Asia, called Asian dust storms (ADS), have been assessed in the past for their effect on health in Asian countries. Our objective was to study the ADS association with asthma symptoms in adult patients in Japan. METHODS: We designed a telephone survey to assess ADS influence on upper and lower respiratory, ocular and cutaneous symptoms in 98 patients with adult asthma from April to May 2007. Peak expiratory flow (PEF) was also measured from February to May. RESULTS: Worsening lower respiratory symptoms were noted by 22 of 98 patients during ADS in April, when Japanese cedar pollen levels also increased. During ADS in May, however, Japanese cedar and cypress pollen levels were not elevated, 11 patients had worsening of lower respiratory symptoms. None required emergency treatment for the exacerbation. Lower respiratory symptoms worsening most were cough and sputum; this was more common in patients with allergic rhinitis or atopy than in those without (P < 0.05). Min%Max differed significantly at 88.7 ± 6.6% during dust dispersion period, defined as the ADS day plus the next 6 days, versus 92.0 ± 5.3% during the 7-day period before a dust storm. CONCLUSIONS: We found that ADS aggravated lower respiratory symptoms in adult patients with asthma, but this influence was mild.

Association with Ambient Air Pollutants and School Absence Due to Sickness in Schoolchildren: A Case-Crossover Study in a Provincial Town of Japan.

The effect of ambient air pollutants and Asian dust (AD) on absence from school due to sickness has not been well researched. By conducting a case-crossover study, this study investigated the influence of ambient air pollutants and desert sand dust particles from East Asia on absence from school due to sickness. From November 2016 to July 2018, the daily cases of absence due to sickness were recorded in five elementary schools in Matsue, Japan. During the study period, a total of 16,915 absence cases were recorded, which included 4865 fever cases and 2458 cough cases. The relative risk of overall absence in a 10-µg/m3 increment of PM2.5 and a 0.1-km-1 of desert sand dust particles from East Asia were found with 1.28 (95%CI: 1.15-1.42) and 2.15 (1.04-4.45) at lag0, respectively. The significant influence of PM2.5 persisted at lag5 and that of desert sand dust particles at lag2. NO2 had statistically significant effects at lag2, lag3, and lag4. However, there was no evidence of a positive association of Ox and SO2 with absence from school. These results suggested that PM2.5, NO2, and AD increased the risk of absence due to sickness in schoolchildren.

Bronchodilator Reversibility Occurring during the Acute Phase of Paragonimiasis westermani Infection.

A 43-year-old woman was referred to our hospital with peripheral blood hypereosinophilia and abnormal chest X-ray findings. Her pleural effusion revealed hypereosinophilia and a low glucose level. She was diagnosed with pulmonary paragonimiasis based on an elevated antibody level of Paragonimiasis westermani. Although she had no medical history of allergic disorders, a pulmonary function test revealed bronchodilator reversibility. After praziquantel therapy, her symptoms, hypereosinophilia in peripheral blood, and pleural effusion were improved. A repeated pulmonary function test after praziquantel therapy showed a negative bronchodilator response. Pulmonary paragonimiasis may induce bronchodilator reversibility during the acute phase of infection.

Nivolumab-induced cholangitis in patients with non-small cell lung cancer: Case series and a review of literature.

Immune checkpoint inhibitors (ICIs), including nivolumab, have exhibited substantial benefits in the treatment of several types of cancers. However, treatment with ICIs is often accompanied by immune-related adverse events (irAEs), and a clear understanding of the precise indications and management of irAEs is important for harnessing the full potential of these agents. While skin- or gastrointestinal-associated irAEs have been relatively well studied, there are few reports regarding nivolumab-induced cholangitis. We retrospectively reviewed data from patients with advanced or recurrent non-small cell lung cancer who were treated with nivolumab between December 2015 and December 2018 at Tottori University in Japan. Among the 59 patients, we identified four patients who experienced nivolumab-induced cholangitis. Of these four patients, stable disease (SD) was observed in two patients (50%), while partial response (PR) was achieved in two patients (50%) under nivolumab treatment. Patients were treated with corticosteroid alone (n=2) or in combination with mycophenolate mofetil (MMF) (n=2); these treatments resulted in improvements in nivolumab-induced cholangitis in three patients. In conclusion, the present retrospective study identified four cases of nivolumab-induced cholangitis. The combination of corticosteroid and MMF was effective in two cases with grade 4 nivolumab-induced cholangitis. Further reports are needed to establish the optimal management of patients with this irAE.

Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines.

PURPOSE: Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer. Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines. EXPERIMENTAL DESIGN: We studied the correlation between EGFR expression in lung cancer cell lines and the ADCC activity of cetuximab as well as the influence of interleukin-2 and chemotherapy on the ADCC activity. EGFR expression was measured by a quantitative flow cytometric analysis and immunohistochemistry. The ADCC activity was assessed by a 4-h (51)Cr release assay. Peripheral blood mononuclear cells, purified T cells, natural killer (NK) cells, and monocytes from healthy donors or lung cancer patients were used as effector cells. RESULTS: Fresh peripheral blood mononuclear cells exhibited cetuximab-mediated ADCC activity against lung cancer cell lines at a low concentration of cetuximab (0.25 microg/mL). A logarithmic correlation was observed between the number of EGFRs and ADCC activity. Even low EGFR expression, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity, and further increases in EGFR expression on the target cells had no further effect on the ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients. CONCLUSIONS: These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients.

[Case of an HTLV-1 carrier complicated with chronic pulmonary histoplasmosis].

A 58-year-old man was admitted with complaints of pain in the right upper right side of the chest. Chest radiography and computed tomography (CT) revealed a cavitary lesion in the right upper lobe. A CT-guided percutaneous lung biopsy and transbronchial lung biopsy of this lesion did not yield a definitive diagnosis; therefore, we performed video assisted thoracic surgery (VATS). We also investigated various types of mycosis because he had several records of overseas travel. At a later day, the histoplasma immunodiffusion test showed positive results. We finally diagnosed pulmonary histoplasmosis based on the clinical course, CT and radiographic images and serological tests. Voriconazole improved the patient's subjective symptoms and laboratory findings. A positive reaction was obtained for anti-human T-cell leukemia virus type 1 (HTLV-1) antibody and the HTLV-1 carrier, confirming his immunodeficiency disorder. We raised the possibility that the development of pulmonary histoplasmosis might be associated with the HTLV-1 carrier.

Ozone augments interleukin-8 production induced by ambient particulate matter.

BACKGROUND: Experimental and controlled human exposure studies have demonstrated additive effects of ambient particulate matter and ozone on health. A few epidemiological studies have suggested that ambient particulate matter components are important for the combined effects of ambient particulate matter and ozone on health. However, few studies have examined whether ozone changes the effects of ambient particulate matter on pro-inflammatory cytokine production. In this study, the influence of ozone on pro-inflammatory cytokine production in response to ambient particulate matter was evaluated. RESULTS: Ambient particulate matter smaller than 1 µm was collected and the suspension of this particulate matter was bubbled through 0.12 ppm and 0.24 ppm ozone. THP1 cells were stimulated by the solution containing the particulate matter with and without bubbling through ozone at 1 µg/mL. The interleukin-8 concentrations in the supernatants of THP1 cells stimulated by collected particulate matter dissolved in solution were 108.3 ± 24.7 pg/mL without ozone exposure, 165.0 ± 26.1 pg/mL for 0.12 ppm ozone bubbling for 1 min, 175.1 ± 33.1 pg/mL for 0.12 ppm for 5 min, 183.3 ± 17.8 pg/mL for 0.12 ppm for 15 min, 167.8 ± 35.9 pg/mL for 0.24 ppm for 1 min, 209.2 ± 8.4 pg/mL for 0.24 ppm for 5 min, and 209.3 ± 14.3 pg/mL for 0.24 ppm for 15 min. Ozone significantly increased interleukin-8 concentrations compared to those for particulate matter dissolved in solution without ozone exposure and the solvent only (8.2 ± 0.9 pg/mL) in an ozone concentration-dependent manner. Collected particulate matter in solutions with or without bubbling through ozone had no effect on interleukin-6 production. The antioxidant N-acetyl-L-cysteine significantly inhibited the increases in interleukin-8 induced by solutions with particulate matter, regardless of ozone exposure. The reactive oxygen species concentration in solutions with collected particulate matter was not associated with ozone bubbling. CONCLUSION: Ozone may augment the production of interleukin-8 in response to ambient particulate matter by a mechanism unrelated to reactive oxygen species. These results support the epidemiological evidence for combined effects of ambient particulate matter and ozone on human health.

A Muscarinic Antagonist Reduces Airway Inflammation and Bronchoconstriction Induced by Ambient Particulate Matter in a Mouse Model of Asthma.

Ambient particulate matter (PM) can increase airway inflammation and induce bronchoconstriction in asthma. This study aimed to investigate the effect of tiotropium bromide, a long-acting muscarinic antagonist, on airway inflammation and bronchoconstriction induced by ambient PM in a mouse model of asthma. We compared the effect of tiotropium bromide to that of fluticasone propionate and formoterol fumarate. BALB/c mice were sensitized to ovalbumin (OVA) via the airways and then administered tiotropium bromide, fluticasone propionate, or formoterol fumarate. Mice were also sensitized to ambient PM via intranasal instillation. Differential leukocyte counts and the concentrations of interferon (IFN)-γ, interleukin (IL)-5, IL-6, IL-13, and keratinocyte-derived chemokine (KC/CXCL1) were measured in bronchoalveolar lavage fluid (BALF). Diacron-reactive oxygen metabolites (dROMs) were measured in the serum. Airway resistance and airway inflammation were evaluated in lung tissue 24 h after the OVA challenge. Ambient PM markedly increased neutrophilic airway inflammation in mice with OVA-induced asthma. Tiotropium bromide improved bronchoconstriction, and reduced neutrophil numbers, decreased the concentrations of IL-5, IL-6, IL-13, and KC/CXCL1 in BALF. However, tiotropium bromide did not decrease the levels of dROMs increased by ambient PM. Though eosinophilic airway inflammation was reduced with fluticasone propionate, neutrophilic airway inflammation was unaffected. Bronchoconstriction was improved with formoterol fumarate, but not with fluticasone propionate. In conclusion, tiotropium bromide reduced bronchoconstriction, subsequently leading to reduced neutrophilic airway inflammation induced by ambient PM.

Association of short-term ozone exposure with pulmonary function and respiratory symptoms in schoolchildren:A panel study in a western Japanese city.

The average annual ozone levels have been increasing in Japan, even though the high ozone levels have decreased in recent years. There is limited information on the relationship between ozone exposure, pulmonary function, and respiratory symptoms in schoolchildren in Japan. The aim of this study was to investigate the effects of short-term ozone exposure on pulmonary function and respiratory symptoms in Japanese schoolchildren. Afternoon peak expiratory flow (PEF) values and respiratory symptom scores were recorded daily in 276 schoolchildren from September to October 2016 and from January to February 2017. The association of daily ozone levels with PEF was assessed using a linear mixed model and that with respiratory symptoms was evaluated by generalized estimating equations logistic regression analysis. There was a significant association of daily ozone levels with PEF values. A 13.6-ppb increment in the interquartile range for ozone exposure was significantly associated with a decrease in PEF of -3.67 L/min (95% confidence interval -4.73, -2.61). However, increased ozone levels were not associated with an increased risk of respiratory symptoms. Our present findings suggest that more attention should be paid to the potential adverse effects of short-term ozone exposure on pulmonary function in schoolchildren. J. Med. Invest. 65:236-241, August, 2018.

Diverse activation states of RhoA in human lung cancer cells: contribution of G protein coupled receptors.

Rho GTPases play an essential role in the control of various cellular functions. Accumulating evidence suggests that RhoA overexpression contributes to human cancer development. However, the activation states of RhoA are poorly defined in cancer cells. In this study, we examined both the expression levels and the activation states of RhoA in various lung cancer cells by quantitative real-time reverse transcriptase-polymerase chain reaction and in vivo Rho guanine nucleotide exchange assay, respectively. Moreover, we dissected the signaling pathway from the cell surface receptors to RhoA using a broad-spectrum G protein coupled receptor (GPCR) antagonist, [D-Arg1,D-Trp5,7,9,Leu11]Substance P (SP), and a recently reported Galphaq/11-selective inhibitor, YM-254890. We found that RhoA was expressed highly in large cell carcinoma cells but only weakly in adenocarcinoma cells. The activation states of RhoA are considerably different from its expression profiles. We found that four of six small cell lung carcinoma (SCLC) cell lines exhibited a moderate to high activation rate of RhoA. The addition of [D-Arg1,D-Trp5,7,9,Leu11]SP reduced RhoA activity by almost 60% in H69 SCLC cells. The addition of YM-254890 had no effect on RhoA activity in H69 cells. Our results suggest that RhoA is activated in various lung cancer cells independent of its expression levels, and the high activation state of RhoA in SCLC cells mainly depends on a neuroendocrine peptide autocrine system which signals through Galpha12 coupled GPCR to RhoA. This study provides new insights into RhoA signaling in lung cancer cells and may help in developing novel therapeutic strategies against lung cancer.