Real Clinical Practice of Combined Atezolizumab Plus Chemotherapy in Patients With Small Cell Lung Cancer.

BACKGROUND/AIM: Atezolizumab, an anti-PD-L1 antibody, has been increasingly administered in combination with chemotherapy to patients with small cell lung cancer (SCLC). This study aimed to determine how patients with extensive disease (ED) -SCLC responded to atezolizumab with chemotherapy and found factors affecting long-term response and survival. PATIENTS AND METHODS: This study focused on patients with SCLC who were treated with a combination of atezolizumab and chemotherapy in Japan between 2019 and 2023. Patient information and tumor response were analyzed, along with adverse events. We compared data and estimated survival probabilities. RESULTS: In our clinical trial, 95 patients with SCLC who received this treatment had a median progression-free survival of 6.0 months and a median overall survival of 15.0 months. Immune-related adverse events were observed in 13.7% of the patients, with grade 3 or higher in 5.3%. The efficacy and immune-related adverse events associated with this treatment regimen were comparable to those reported in previous clinical trials. Progression-free survival >2 years was observed in a small number of patients (5.3%). CONCLUSION: Our research will offer important insights for the future care of patients with extensive-stage SCLC by utilizing atezolizumab in combination with chemotherapy. Accumulation and confirmation of clinical practice results will have important implications for the future implementation of this therapy.

Inflammatory myofibroblastic tumor directly invading the right first rib treated with oral steroids: a case report.

BACKGROUND: We present a case of an inflammatory myofibroblastic tumor cured with a short period of steroid administration, a treatment previously unreported for such cases. CASE PRESENTATION: A 49-year-old man had a chief complaint of chest pain for more than 3 days. Computed tomography (CT) revealed a tumoral lesion suspected to have infiltrated into the right first rib and intercostal muscles, with changes in lung parenchymal density around the lesion. The maximal standardized uptake value on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography was high (16.73), consistent with tumor presence. CT-guided biopsy revealed an inflammatory myofibroblastic tumor with no distant metastases. Surgery was indicated based on the disease course. However, he had received an oral steroid before the preoperative contrast-enhanced CT scan due to a history of bronchial asthma, and subsequent CT showed that the tumor shrank in size after administration; he has been recurrence-free for more than a year. CONCLUSIONS: Surgery is still the first choice for inflammatory myofibroblastic tumors, as the disease can metastasize and relapse; however, this condition can also be cured with a short period of steroid therapy.

Patient profiling to predict response to bronchial thermoplasty in patients with severe asthma.

Bronchial thermoplasty is the only device-based nonpharmacological treatment approach for severe asthma. Current guidelines are cautious in recommending bronchial thermoplasty because of unknown patient response prediction. Recent research on bronchial thermoplasty includes up-to-date, state-of-the-art, and recent-advances reviews. However, these reviews provide a broad and general discussion on equipment, technique, patient selection, and patient management, with little evaluation of the predictors of a beneficial response. Predicting an optimal response to bronchial thermoplasty in patients with severe asthma remains elusive. The lack of reliable predictive markers means that bronchial thermoplasty remains a last-line treatment and makes profiling for predicting the response or efficacy a topic of study. Genetic changes are associated with airway remodeling. A gap in the literature exists regarding patient profiling to predict the response to bronchial thermoplasty in patients with severe asthma. Therefore, recently published omics data and genetic associations regarding the response to bronchial thermoplasty therapy should be reviewed. We present an up-to-date review of recent publications profiling the response to bronchial thermoplasty in patients with severe asthma.

A case of epidermal growth factor receptor tyrosine kinase inhibitor effectiveness in epidermal growth factor receptor mutation-positive squamous cell carcinoma.

A 71-year-old non-smoker woman was admitted to our hospital because of left front chest pain. A computed tomography scan showed a large mass of >7.0 cm in the lower left part of the lung and multiple organ metastases in the liver, brain, bone, and left adrenal gland. Pathological analysis of a resected specimen obtained by bronchoscopy revealed keratinization. In addition, p40 was positive and thyroid transcription factor-1, synaptophysin, CD56, and chromogranin A were negative by immunohistochemistry. Programmed cell death ligand 1 expression was 1%-10%, and exon 19 deletion was detected. We diagnosed the patient with stage IVB lung squamous cell carcinoma and administered osimertinib. Osimertinib was later replaced with afatinib because of grade 3 skin rash. Overall, the size of the cancer was decreased. Furthermore, her symptoms, laboratory data, and computer tomographic findings markedly improved. In summary, we experienced a case of epidermal growth factor receptor-positive lung squamous cell carcinoma that was responsive to epidermal growth factor receptor tyrosine kinase inhibitors.

ELOVL6 deficiency aggravates allergic airway inflammation through the ceramide-S1P pathway in mice.

BACKGROUND: Elongation of very-long-chain fatty acids protein 6 (ELOVL6), an enzyme regulating elongation of saturated and monounsaturated fatty acids with C12 to C16 to those with C18, has been recently indicated to affect various immune and inflammatory responses; however, the precise process by which ELOVL6-related lipid dysregulation affects allergic airway inflammation is unclear. OBJECTIVES: This study sought to evaluate the biological roles of ELOVL6 in allergic airway responses and investigate whether regulating lipid composition in the airways could be an alternative treatment for asthma. METHODS: Expressions of ELOVL6 and other isoforms were examined in the airways of patients who are severely asthmatic and in mouse models of asthma. Wild-type and ELOVL6-deficient (Elovl6-/-) mice were analyzed for ovalbumin-induced, and also for house dust mite-induced, allergic airway inflammation by cell biological and biochemical approaches. RESULTS: ELOVL6 expression was downregulated in the bronchial epithelium of patients who are severely asthmatic compared with controls. In asthmatic mice, ELOVL6 deficiency led to enhanced airway inflammation in which lymphocyte egress from lymph nodes was increased, and both type 2 and non-type 2 immune responses were upregulated. Lipidomic profiling revealed that the levels of palmitic acid, ceramides, and sphingosine-1-phosphate were higher in the lungs of ovalbumin-immunized Elovl6-/- mice compared with those of wild-type mice, while the aggravated airway inflammation was ameliorated by treatment with fumonisin B1 or DL-threo-dihydrosphingosine, inhibitors of ceramide synthase and sphingosine kinase, respectively. CONCLUSIONS: This study illustrates a crucial role for ELOVL6 in controlling allergic airway inflammation via regulation of fatty acid composition and ceramide-sphingosine-1-phosphate biosynthesis and indicates that ELOVL6 may be a novel therapeutic target for asthma.

A Ruptured Left Gastric Artery Aneurysm That Neoplasticized during the Course of Coronavirus Disease 2019: A Case Report.

Coronavirus disease 2019 (COVID-19) is an acute respiratory syndrome caused by SARS-CoV-2 and is known to cause respiratory and systemic symptoms. A SARS-CoV-2 infection is involved in aneurysm formation, enlargement, and rupture in medium-sized vessels, such as the cerebral and coronary arteries and the aorta. In contrast, its involvement in forming aneurysms in medium-sized vessels other than the cerebral and coronary arteries has not been reported. An 84-year-old Japanese man with COVID-19 was admitted to our hospital. The treatment course was favorable, and the COVID-19 treatment was completed by the 10th day. On day 14, pancreatic enzymes increased mildly. An abdominal computed tomography revealed a ruptured left gastric aneurysm after spontaneous hemostasis. Arterial embolization was performed. In this patient, a new left gastric aneurysm was suspected of having formed and ruptured during the course of the COVID-19 treatment. To the best of our knowledge, this is the first report of abdominal visceral aneurysm formation caused by COVID-19 in a medium-sized vessel, and it is necessary to remember that aneurysms can be formed at any site when treating this syndrome.

Transcriptome genetic differences between responders and non-responders before bronchial thermoplasty.

BACKGROUND: Bronchial thermoplasty (BT) is an endoscopic therapy used for the treatment of refractory asthma. Some predictive factors, for example the number of activations and severity of disease at baseline, have been used to determine the effectiveness of BT in treating patients with asthma. The aim of the present study was to comprehensively analyze RNA samples from the airway bronchial tissues of patients with severe asthma treated by BT, and to characterize each patient as a BT responder or non-responder. METHODS: Eight patients with severe asthma scheduled to undergo BT and bronchus biopsies were recruited before the procedures were conducted. Extracted RNA samples from bronchial tissues were sequenced and differential gene expression analysis was carried out.Results/discussion: Subjects with Asthma Quality of Life Questionnaire score changes ≥0.5 for a period of 12 months were considered BT responders. Non-responders had score changes <0.5 for 12 months. Histopathology findings were similar to those reported previously, and no significant differences in the expression of α-smooth muscle actin and protein gene product 9.5 were observed between responders and non-responders. Transcriptome analysis at baseline identified 67 genes that were differentially expressed between responders and non-responders, including SLPI, MMP3, and MUC19, which were upregulated in responders. Although the differentially expressed gene products may have conflicting effects, genes in the airway epithelium and extracellular matrix of patients with severe asthma may determine the BT response. Our results identified possible transcriptomic changes that could be used to identify BT responders.

Cellular Source of Cysteinyl Leukotrienes Following Chlorine Exposure.

Exposure of mice to high concentrations of chlorine leads to the synthesis of cysteinyl leukotrienes (cysLTs). CysLTs contribute to chlorine-induced airway hyperresponsiveness. The aim of the current study was to determine the cellular source of the cysLTs. To achieve this aim, we exposed mice to 100 ppm of chlorine for 5 minutes. Intranasal instillation of clodronate in liposomes and of diphtheria toxin in CD11c-DTR mice was used to deplete macrophages. CCR2-/- mice were used to assess the contribution of recruited macrophages. Eosinophils and neutrophils were depleted with specific antibodies. Platelet-neutrophil aggregation was prevented with an antibody against P-selectin. The potential roles of phagocytosis of neutrophils by macrophages and of transcellular metabolism between epithelial cells and neutrophils were explored in coculture systems. We found that depletion of neutrophils was the only intervention that inhibited the synthesis of cysLTs at 24 hours after chlorine exposure. Although macrophages did synthesize cysLTs in response to phagocytosis of neutrophils, depletion of macrophages did not reduce the increment in cysLTs triggered by chlorine exposure. However, coculture of airway epithelial cells with neutrophils resulted in a significant increase in the synthesis of cysLTs, dependent on the expression of 5-lipoxygenase by neutrophils. We conclude that cysLT synthesis following chlorine exposure may be dependent on transcellular metabolism by neutrophil-epithelial interactions.

Pneumonitis Due to Oren-gedoku-to (Coptis Detoxifying Decoction).

A 54-year-old man started to take oren-gedoku-to (coptis detoxifying decoction) because he was experiencing chronic hot flashes, night sweats and insomnia. He developed a high fever from the day of intake. At day 17, he stopped taking oren-gedoku-to because of malaise and chills, and he was admitted to our hospital. Drug-induced pneumonitis was suspected, and all drugs were stopped. Consequently, his symptoms, laboratory data and chest X-ray findings markedly improved. The results of a lymphocyte stimulation test were positive for oren-gedoku-to and one of its components, ougon (Baikal skullcap). Based on these findings, we diagnosed him with pneumonitis caused by ougon.

Tolerogenic signaling of alveolar macrophages induces lung adaptation to oxidative injury.

BACKGROUND: Inhaled oxidative toxicants present in ambient air cause airway epithelial injury, inflammation, and airway hyperresponsiveness. Effective adaptation to such environmental insults is essential for the preservation of pulmonary function, whereas failure or incomplete adaptation to oxidative injury can render the host susceptible to the development of airway disease. OBJECTIVE: We sought to explore the mechanisms of airway adaptation to oxidative injury. METHODS: For a model to study pulmonary adaptation to oxidative stress-induced lung injury, we exposed mice to repeated nose-only chlorine gas exposures. Outcome measures were evaluated 24 hours after the last chlorine exposure. Lung mechanics and airway responsiveness to methacholine were assessed by using the flexiVent. Inflammation and antioxidant responses were assessed in both bronchoalveolar lavage fluid and lung tissue. Using both loss or gain of function and genomic approaches, we further dissected the cellular and molecular mechanisms involved in pulmonary adaptation. RESULTS: Repeated exposures to oxidative stress resulted in pulmonary adaptation evidenced by abrogation of neutrophilic inflammation and airway hyperresponsiveness. This adaptation was independent of antioxidant mechanisms and regulatory T cells but dependent on residential alveolar macrophages (AMs). Interestingly, 5% of AMs expressed forkhead box P3, and depletion of these cells abolished adaptation. Results from transcriptomic profiling and loss and gain of function suggest that adaptation might be dependent on TGF-ß and prostaglandin E2. CONCLUSION: Pulmonary adaptation during oxidative stress-induced lung injury is mediated by a novel subset of forkhead box P3-positive AMs that limits inflammation, favoring airway adaptation and host fitness through TGF-ß and prostaglandin E2.

Montelukast reduces inhaled chlorine triggered airway hyperresponsiveness and airway inflammation in the mouse.

BACKGROUND AND PURPOSE: Cysteinyl leukotrienes (CysLTs) are pro-inflammatory lipid mediators that exacerbate disease state in several asthma phenotypes including asthma induced by allergen, virus and exercise. However, the role of CysLTs in irritant-induced airway disease is not well characterized. The purpose of the current study was to investigate the effect of montelukast, a CysLT1 receptor antagonist, on parameters of irritant-induced asthma induced by inhalation of chlorine in the mouse. EXPERIMENTAL APPROACH: BALB/c mice were exposed to chlorine in air (100 ppm, for 5 min). Montelukast (3 mg·kg-1 ) or the vehicle (1% methylcellulose) was administered 24 and 1 h prior to chlorine exposure and 1 h prior to outcome measurements. Twenty-four hours after exposure, responses to inhaled aerosolized methacholine, cell composition and an array of cytokines/chemokines in bronchoalveolar lavage (BAL) fluid were measured. Neutralizing antibodies against IL-6 and VEGF were administered prior to exposures. KEY RESULTS: Montelukast reduced chlorine -induced airway hyperresponsiveness (AHR) to methacholine in the peripheral lung compartment as estimated from dynamic elastance, but not in large conducting airways. Montelukast treatment attenuated chlorine-induced macrophage influx, neutrophilia and eosinophilia in BAL fluid. Chlorine exposure increased VEGF, IL-6, the chemokines KC and CCL3 in BAL fluid. Montelukast treatment prevented chlorine-induced increases in VEGF and IL-6. Anti-IL-6 antibody inhibited chlorine-induced neutrophilia and reduced AHR. CONCLUSIONS AND IMPLICATIONS: Pre-treatment with montelukast attenuated chlorine-induced neutrophilia and AHR in mice. These effects are mediated, in part, via IL-6.

Inflammation and airway hyperresponsiveness after chlorine exposure are prolonged by Nrf2 deficiency in mice.

RATIONALE: Chlorine gas (Cl2) is a potent oxidant and trigger of irritant induced asthma. We explored NF-E2-related factor 2 (Nrf2)-dependent mechanisms in the asthmatic response to Cl2, using Nrf2-deficient mice, buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis and sulforaphane (SFN), a phytochemical regulator of Nrf2. METHODS: Airway inflammation and airway hyperresponsiveness (AHR) were assessed 24 and 48h after a 5-min nose-only exposure to 100ppm Cl2 of Nrf2-deficient and wild type Balb/C mice treated with BSO or SFN. Animals were anesthetized, paralyzed and mechanically ventilated (FlexiVent™) and challenged with aerosolized methacholine. Bronchoalveolar lavage (BAL) was performed and lung tissues were harvested for assessment of gene expression. RESULTS: Cl2 exposure induced a robust AHR and an intense neutrophilic inflammation that, although similar in Nrf2-deficient mice and wild-type mice at 24h after Cl2 exposure, were significantly greater at 48h post exposure in Nrf2-deficient mice. Lung GSH and mRNA for Nrf2-dependent phase II enzymes (NQO-1 and GPX2) were significantly lower in Nrf2-deficient than wild-type mice after Cl2 exposure. BSO reduced GSH levels and promoted Cl2-induced airway inflammation in wild-type mice, but not in Nrf2-deficient mice, whereas SFN suppressed Cl2-induced airway inflammation in wild-type but not in Nrf2-deficient mice. AHR was not affected by either BSO or SFN at 48h post Cl2 exposure. CONCLUSIONS: Nrf2-dependent phase II enzymes play a role in the resolution of airway inflammation and AHR after Cl2 exposure. Moderate deficiency of GSH affects the magnitude of acute inflammation but not AHR.

Overexpression of RORγt Enhances Pulmonary Inflammation after Infection with Mycobacterium Avium.

Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial disease in humans. The role of Th17 immunity in the pathogenesis of intracellular bacteria, such as MAC, is not currently understood. Transcription factor RAR-related orphan receptor gamma t (RORγt) is known as the master regulator for Th17 cell development. Here, we investigated the role of RORγt in host responses against MAC infection. Wild-type (WT) mice and RORγt-overexpressing mice were infected with MAC via intratracheal inoculation. Systemic MAC growth was not different between WT mice and RORγt-overexpressing mice. However, neutrophilic pulmonary inflammation following MAC infection was enhanced in RORγt-overexpressing mice compared with that in WT mice. The cytokine expression shifted toward a Th17 phenotype in the lungs of RORγt-overexpressing mice following MAC infection; the levels of IL-6 and IL-17 were significantly higher in the lung of these mice than in WT mice. In addition to the increase in IL-17 single-positive T cells, T cells producing both IL-17 and interferon-γ were elevated in the lung of RORγt-overexpressing mice following MAC infection. These findings suggest that RORγt overexpression-mediated Th17 bias contributes to local inflammation rather than systemic responses, by regulating neutrophil recruitment into the sites of infection during MAC infection.

Role of Th1/Th17 balance regulated by T-bet in a mouse model of Mycobacterium avium complex disease.

Th1 immune responses are thought to be important in protection against intracellular pathogens. T-bet is a critical regulator for Th1 cell differentiation and Th1 cytokine production. The aim of this study was to determine the role of T-bet in host defense against Mycobacterium avium complex (MAC) infection. Wild-type mice, T-bet-deficient mice, and T-bet-overexpressing mice were infected with MAC via intratracheal inoculation. Macrophages and dendritic cells obtained from these mice were incubated with MAC. T-bet-deficient mice were highly susceptible to MAC, compared with wild-type mice and T-bet-overexpressing mice. Neutrophilic pulmonary inflammation was also enhanced in T-bet-deficient mice, but attenuated in T-bet-overexpressing mice, following MAC infection. Cytokine expression shifted toward Th1 in the lung and spleen of T-bet-overexpressing mice, but toward Th17 in T-bet-deficient mice. IFN-γ supplementation to T-bet-deficient mice reduced systemic MAC growth but did not reduce pulmonary inflammation. In contrast, neutralization of IL-17 in T-bet-deficient mice reduced pulmonary inflammation but did not affect mycobacterial growth in any organs tested. T-bet-deficient T cells tended to differentiate toward Th17 cells in vitro following exposure to MAC. Treatment with NO donor suppressed MAC-induced Th17 cell differentiation of T-bet-deficient T cells. This study identified that the fine balance between Th1 and Th17 responses is essential in defining the outcome of MAC disease. T-bet functions as a regulator for Th1/Th17 balance and is a critical determinant for host resistance to MAC infection by controlling cytokine and NO levels.

Carbocisteine reduces virus-induced pulmonary inflammation in mice exposed to cigarette smoke.

Carbocisteine (S-CMC) inhibits viral infection and prevents acute exacerbation of chronic obstructive pulmonary disease. We recently demonstrated the protective effects of NF-E2-related factor (Nrf) 2 against influenza virus (FluV)-induced pulmonary inflammation in mice exposed to cigarette smoke (CS). In our current study, we investigated the effects of S-CMC on Nrf2 activation in cultured macrophages, and in mice infected with influenza after exposure to CS. Nuclear translocation of Nrf2 and the expression of Nrf2-targeted antioxidant genes, such as heavy and light subunits of γ glutamyl cysteine synthetase and heme oxigenase-1, were enhanced in a dose-dependent manner after treatment with S-CMC in peritoneal and alveolar macrophages of wild-type mice, but not in those of Nrf2-deficient mice. Nuclear translocation of Nrf2 in macrophages was inhibited by the phosphatidylinositol 3-kinase inhibitor, LY294002. Phosphorylated Akt, Nrf2, and heme oxigenase-1 were induced in the alveolar macrophages of the lungs in wild-type mice after S-CMC administration. The extent of oxidative stress, inflammatory cell infiltration, pulmonary edema, and goblet cell hyperplasia was suppressed by S-CMC administration in the lungs of wild-type mice after exposure to both CS and FluV. Our findings suggest that S-CMC reduces pulmonary inflammation and mucus overproduction in mice exposed to CS after infection with FluV via the activation of Nrf2.

SQSTM1/p62/A170 regulates the severity of Legionella pneumophila pneumonia by modulating inflammasome activity.

Sequestosome1/A170/p62 (SQSTM1) is a scaffold multifunctional protein involved in several cellular events, such as signal transduction, cell survival, cell death, and inflammation. SQSTM1 expression by macrophages is induced in response to environmental stresses; however, its role in macrophage-mediated host responses to environmental stimuli, such as infectious pathogens, remains unclear. In this study, we investigated the role of SQSTM1 in host responses to Legionella pneumophila, an intra-cellular pathogen that infects macrophages, in both an SQSTM1-deficient (SQSTM1(-/-) ) mouse model and macrophages from these mice. Compared with wild-type (WT) macrophages, the production and secretion of the proinflammatory cytokine IL-1ß was significantly enhanced in SQSTM1(-/-) macrophages after infection with L. pneumophila. Inflammasome activity, indicated by the level of IL-18 and caspase-1 activity, was also elevated in SQSTM1(-/-) macrophages after infection with L. pneumophila. SQSTM1 may interact with nucleotide-binding oligomerization domain-like receptor family, caspase recruitment domain-containing 4 and nucleotide-binding oligomerization domain like receptor family, pyrin domain containing 3 proteins to inhibit their self-dimerization. Acute pulmonary inflammation induced by L. pneumophila and silica was enhanced in SQSTM1(-/-) mice with an increase in IL-1ß levels in the bronchoalveolar lavage fluids. These findings suggest that SQSTM1 is a negative regulator of acute pulmonary inflammation, possibly by regulating inflammasome activity and subsequent proinflammatory cytokine production.

Defecation-related asthma.

We herein report the case of a 39-year-old man with recurrent asthma exacerbations preceded by abdominal cramps with the urge to defecate. The patient had a history of near-fatal asthma associated with these gastrointestinal symptoms starting five years before his admission. He stated that, even when his daily asthma symptoms were under control, he suffered from attacks, especially when he had a strong urge to defecate. Although the contribution of increased parasympathetic tone to the onset of bronchospasms was likely, anticholinergics were not effective. Instead, the patient's symptoms successfully improved following the prophylactic use of laxatives, which might therefore be an appropriate therapeutic option for this type of asthma.

Transcription factors GATA-3 and RORγt are important for determining the phenotype of allergic airway inflammation in a murine model of asthma.

In refractory asthma, neutrophils, rather than eosinophils, often predominate in the airways. Neutrophilic airway inflammation appears to be resistant to steroids and may be related to the Th17, rather than the Th2, cytokine milieu. However, the role of GATA-3 and RORγt, transcription factors for Th2 and Th17 cell differentiation, respectively, in the pathogenesis of steroid-insensitive asthma remains unclear. To examine the effect of GATA-3- and RORγt-overexpression backgrounds on airway inflammation and steroid sensitivity, we generated two strains of transgenic mice overexpressing GATA-3 or RORγt. Mice were sensitized and challenged with OVA. Some OVA-sensitized/challenged mice were treated with dexamethasone, anti-IL-17 Ab, CXCR2 antagonist, or anti-IL-6R Ab to demonstrate their therapeutic effects on airway inflammation. Although Ag-specific airway inflammation and hyperresponsiveness were induced in each mouse, the phenotype of inflammation showed a distinct difference that was dependent upon the genotype. GATA-3-overexpressing mice exhibited steroid-sensitive eosinophilic inflammation with goblet cell hyperplasia and mucus hyperproduction under Th2-biased conditions, and RORγt-overexpressing mice developed steroid-insensitive neutrophilic inflammation under Th17-biased conditions. The levels of keratinocyte-derived chemokine, MIP-2, IL-6, and other neutrophil chemotaxis-related mediators were significantly elevated in OVA-exposed RORγt-overexpressing mice compared with wild-type mice. Interestingly, airway hyperresponsiveness accompanied by neutrophilic airway inflammation in RORγt-overexpressing mice was effectively suppressed by anti-IL-17 Ab, CXCR2 antagonist, or anti-IL-6R Ab administration. In conclusion, our results suggest that the expression levels of GATA-3 and RORγt may be important for determining the phenotype of asthmatic airway inflammation. Furthermore, blockade of the Th17-signaling pathway may be a treatment option for steroid-insensitive asthma.

Th17-associated cytokines as a therapeutic target for steroid-insensitive asthma.

Steroid-insensitive asthma is an infrequent but problematic airway disease that presents with persistent symptoms, airflow limitation, or recurrent exacerbations even when treated with steroid-based therapies. Because of unsatisfactory results obtained from currently available therapies for steroid-insensitive asthma, a better understanding of its pathogenesis and the development of new targeted molecular therapies are warranted. Recent studies indicated that levels of interleukin (IL)-17 are increased and both eosinophils and neutrophils infiltrate the airways of severe asthmatics. IL-17 is a proinflammatory cytokine mainly secreted from helper T (Th) 17 cells and is important for the induction of neutrophil recruitment and migration at sites of inflammation. This review focuses on the pathogenetic role of Th17 cells and their associated cytokines in steroid-insensitive asthma and discusses the prospects of novel therapeutic options targeting the Th17 signaling pathway.