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.

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.

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.

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.

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.

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.

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.

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.

Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice.

Influenza virus is a common respiratory tract viral infection. Although influenza can be fatal in patients with chronic pulmonary diseases such as chronic obstructive pulmonary disease, its pathogenesis is not fully understood. The Nrf2-mediated antioxidant system is essential to protect the lungs from oxidative injury and inflammation. In the present study, we investigated the role of Nrf2 in protection against influenza virus-induced pulmonary inflammation after cigarette smoke exposure with both in vitro and in vivo approaches. For in vitro analyses, peritoneal macrophages isolated from wild-type and Nrf2-deficient mice were treated with poly(I:C) and/or cigarette smoke extract. For in vivo analysis, these mice were infected with influenza A virus with or without exposure to cigarette smoke. In Nrf2-deficient macrophages, NF-κB activation and the induction of its target inflammatory genes were enhanced after costimulation with cigarette smoke extract and poly(I:C) compared with wild-type macrophages. The induction of antioxidant genes was observed for the lungs of wild-type mice but not those of Nrf2-deficient mice after cigarette smoke exposure. Cigarette smoke-exposed Nrf2-deficient mice showed higher rates of mortality than did wild-type mice after influenza virus infection, with enhanced peribronchial inflammation, lung permeability damage, and mucus hypersecretion. Lung oxidant levels and NF-κB-mediated inflammatory gene expression in the lungs were also enhanced in Nrf2-deficient mice. Our data indicate that the antioxidant pathway controlled by Nrf2 is pivotal for protection against the development of influenza virus-induced pulmonary inflammation and injury under oxidative conditions.

Malignant meningitis secondary to lung adenocarcinoma: an unusual relapse.

We describe a 64-year-old man with locally advanced lung adenocarcinoma who had meningeal relapse soon after the completion of intensive chemo-radiotherapy. Diagnosis of the malignant meningitis was established by cytological examination of the cerebrospinal fluid, which showed malignant cells consistent with adenocarcinoma from the primary site. Although very rare, it is possible that successful chemo-radiotherapy for locally advanced lung cancer could not prevent malignant meningitis as observed in our patient. Physicians should consider performance of brain MRI or contrast CT of the brain and a lumbar puncture to exclude the diagnosis of malignant meningitis, an uncommon but devastating complication of malignancy.