Inflammasome-Independent and Atypical Processing of IL-1ß Contributes to Acid Aspiration-Induced Acute Lung Injury.

Inflammation plays a pivotal role in the pathophysiology of gastric aspiration-induced acute lung injury (ALI). However, its mechanism remains unclear. In this study, we investigated the role of NLRP3 inflammasome-driven IL-1ß production in a mouse model of acid aspiration-induced inflammation and ALI. Acid aspiration-induced inflammatory responses and ALI in wild-type mice were significantly attenuated in IL-1ß-/- mice, but not NLRP3-/- mice. In vitro experiments revealed that severe acidic stress (pH 1.75) induced the processing of pro-IL-1ß into its 18-kDa mature form (p18-IL-1ß), which was different from the caspase-1-processed 17-kDa form (p17-IL-1ß), in human THP-1 macrophages and primary murine macrophages. Deficiency of NLRP3 and caspase-1 had no effect on acidic stress-produced IL-1ß. The production of IL-1ß by severe acidic stress was prevented by inhibitors of serine proteases [4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride], but not of cysteine proteases (E-64), cathepsin G, or inflammasome. The cathepsin D inhibitor pepstatin A inhibited IL-1ß production induced by mild acidic stress (pH 6.2) or lactic acid, but not severe acidic stress. Using mass spectrometry and processing-site mutants of pro-IL-1ß, we identified D109 as a novel cleavage site of pro-IL-1ß in response to severe acidic stress and calculated the theoretical molecular mass of the mature form to be 18.2 kDa. The bioactivity of acidic stress-produced IL-1ß was confirmed by its ability to promote p38 phosphorylation and chemokine upregulation in alveolar epithelial cells. These findings demonstrate a novel mechanism of acid-induced IL-1ß production and inflammation independent of NLRP3 inflammasome and provide new insights into the therapeutic strategies for aspiration pneumonitis and ALI.

Pulmonary mucoepidermoid carcinoma arising in a patient with Kartagener syndrome.

BACKGROUND: Kartagener syndrome, an autosomal recessive disorder with a triad of chronic sinusitis, bronchiectasis, and situs inversus, is characterized by recurrent respiratory tract infections and chronic inflammation of the lung. Information on comorbidities other than infections in patients with Kartagener syndrome is currently limited. CASE PRESENTATION: A 39-year-old, non-smoking female was diagnosed with Kartagener syndrome and admitted to Saitama Medical Center, Jichi Medical University, Japan. Computed tomography revealed an endobronchial massive shadow at the ostial site of the right upper lobe bronchus with atelectasis of the right upper lobe. The mass was surgically resected and pathologically diagnosed as mucoepidermoid carcinoma. The lesion had no vascular invasions and no metastases to the lungs or lymph nodes. The surgical margin was negative for carcinoma. Following surgery, the patient has been in good condition. CONCLUSIONS: The present case showed different clinicopathological characteristics from those previously reported in cases of Kartagener syndrome complicated by carcinoma. To the best of our knowledge, this is the first reported case of a young, non-smoking female with comorbid Kartagener syndrome and pulmonary mucoepidermoid carcinoma. This case report may provide a new perspective on the complications of Kartagener syndrome.

Distinct Benefit of Overall Survival between Patients with Non-Small-Cell Lung Cancer Harboring EGFR Exon 19 Deletion and Exon 21 L858R Substitution.

BACKGROUND: Exon 19 deletion (Del19) and exon 21 L858R substitution (L858R), which account for 90% of epidermal growth factor receptor (EGFR) mutations as common mutations, are associated with favorable outcomes with EGFR-tyrosine kinase inhibitors (TKIs) compared with other uncommon EGFR mutations in non-small-cell lung cancer (NSCLC). However, whether there are differences in overall survival (OS) between patients with these common EGFR mutations remains controversial. METHODS: The subjects studied were 74 NSCLC patients with common EGFR mutations treated with gefitinib or erlotinib. Using univariate and multivariate analyses, we retrospectively compared the clinicopahological characteristics of patients harboring Del19 with those harboring L858R. RESULTS: Compared with patients harboring L858R, EGFR-TKIs provided a significant OS benefit in patients harboring Del19 (p = 0.024), as well as favorable therapeutic responses (p = 0.045) and progression-free survival (PFS) benefits (p = 0.031). In multivariate analyses, Del19 was independently associated with PFS (p = 0.029) and OS (p = 0.009), whereas no parameters other than pleural dissemination at the initial treatment were associated with EGFR mutation types. CONCLUSION: Del19 and L858R have distinct prognostic implications and may require individual therapeutic strategies.

[A case of desquamative interstitial pneumonia in the fibrotic stage].

A 39-year-old man with bronchial asthma was admitted because of fever, muscle pain and body weight loss. Chest CT showed ground-glass opacification, multiple lung cysts and fine reticulation with traction bronchiectasis predominantly in the bilateral lower lobes. Histopathological findings from video-assisted thoracoscopic surgical biopsy showed severe fibrosis of the alveolar wall, interstitial fibrosis which appeared to be of similar duration, and accumulation of eosinophils and macrophages in the alveolar spaces. According to the ATS consensus classification of desquamative interstitial pneumonia (DIP), there is little fibrosis with only mild or moderate thickening of alveolar walls and no scarring fibrosis causing remodeling of the lung architecture. This case was compatible with the ATS consensus classification of desquamative interstitial pneumonia (DIP) without severe fibrosis of the alveolar wall. Finally, we diagnosed DIP in the fibrosing stage because the findings of chest CT were typical and the pathological findings showed the presence of increased amounts of cuboidal epithelium hyperplasia and intraalveolar acidophilic macrophages within a part of moderate interstitial fiblosis. Then we started orally corticosteroid therapy, and as a result he responded well.

[A rare case of primary Sjögren's syndrome complicated by secondary lymphoid interstitial pneumonia].

A 61-year-old woman was referred to our hospital because of an abnormal chest X-ray shadow. She was diagnosed as having primary Sjögren's syndrome based on sicca syndrome, polyclonal hyper-gamma-globulinemia, and positive results for anti-Ro/SS-A and anti-La/SS-B antibodies. Her chest CT scan revealed bilateral ground-glass shadows and septal thickning in the lower lung field (Fig. 2a). Biopsy specimens obtained by video-assisted thoracoscopy (VATS) showed a dense interstitial lymphoid infiltrate, including lymphocytes and plasma cells, predominantly in the alveolar septae (Fig. 3, a-c). Malignant lymphoma was excluded on the basis of immunohistopathological studies (Fig. 4). A diagnosis of lymphoid interstitial pneumonia was made according to the 2002 American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification (International Classification). After administration of prednisolone and azathioprin, the ground-glass shadows on the chest CT rapidly improved (Fig. 2b). The clinico-radiologic-pathologic diagnosis based on the VATS procedure and the International Classification is appropriate and effective for treating collagen vascular disease-associated interstitial lung disease.

Rapid Progression of Lung Cancer Following Emergency Caesarean Section Led to Postpartum Acute Respiratory Failure.

Our case patient was a 38-year-old pregnant Japanese woman who underwent emergency Caesarean section because of massive vaginal bleeding due to a low-lying placenta. Immediately after delivery, she presented with rapidly progressive dyspnea. Contrast-enhanced computed tomography revealed bilateral pleural effusion, lung nodules, multiple liver tumors, and multiple osteolytic lesions. Accordingly, epidermal growth factor receptor-mutant advanced lung adenocarcinoma was diagnosed. This report highlights the occurrence of rapid progression of lung cancer following delivery that led to postpartum acute respiratory failure, rather than due to pulmonary thromboembolism associated with the existing deep venous thrombosis of the inferior vena cava.

Advanced Lung Adenocarcinoma with Nivolumab-associated Dermatomyositis.

We herein report a 42-year-old man with advanced lung adenocarcinoma and nivolumab-associated dermatomyositis. Nivolumab, an anticancer drug that is classified as an immune checkpoint inhibitor, often induces immune-related adverse events (irAEs). However, there have so far been no reports regarding nivolumab-associated dermatomyositis. This patient was diagnosed with dermatomyositis due to the presence of proximal muscle weakness with abnormal electromyography and magnetic resonance imaging findings; skin lesions, such as heliotrope rash, shawl sign, and periungual erythema; and an elevated serum aldolase level after nivolumab administration. It is important to consider drug-associated dermatomyositis in the differential diagnosis of patients presenting with skin lesions and muscle weakness after nivolumab treatment.

A case of hypomyopathic dermatomyositis associated with rapid progressive interstitial pneumonia resistant to multi-immunosuppressive therapy.

The prognosis of interstitial pneumonia in patients with dermatomyositis is thought to depend on the histologic type and response to therapy. We report a case of hypomyopathic dermatomyositis with rapid development of a fatal interstitial pneumonia. Although the histology of lung biopsy indicated minimal alveolitis, the patient died despite multi-immunosuppressive therapy. The autopsy revealed acute and organizing diffuse alveolar damage. In this case, the lung biopsy taken before the acute deterioration did not predict the patient's poor prognosis. Interstitial pneumonia in patients with amyopathic or hypomyopathic dermatomyositis would develop rapidly progressive and refractory. We need larger and better prospective studies to determine whether early and intensive immunosuppressive therapy improves the prognosis of interstitial pneumonia in patients with amyopathic or hypomyopathic dermatomyositis.

[A case of airway-limiting type relapsing polychondritis].

A 59-year-old woman was referred to our hospital for chronic cough and myalgia. Polymyalgia rheumatica (PMR) and bronchial asthma were first diagnosed, and she was prescribed 15 mg/day prednisolone. PMR improved immediately. However, her chronic cough continued, and wheezing was heard on chest auscultation. The flow-volume loop showed a severe expiratory flow limitation and a notching sign at early expiration. Diffuse thickening and narrowing at the trachea and bilateral main bronchus were shown on chest CT. On flexible bronchoscope the trachea and bilateral main bronchus collapsed on expiration. We suspected relapsing polychondritis (RP), but she had no findings of saddle nose or deformity of the external ear. Therefore, biopsy of the tracheal cartilage was done. RP was diagnosed by the modified criteria of Damiani and the histology confirmed degeneration of the tracheal cartilage. She was treated by high dose corticosteroids, and her symptoms improved. This case report emphasizes the need to consider the possibility of RP as a cause of chronic cough or intractable asthma.

A young immunocompetent patient with spontaneous Aspergillus empyema who developed severe eosinophilia.

Aspergillus empyema is usually reported as a complication of surgical procedures, and spontaneous cases are quite rare. Here, we describe the case of a 16-year-old man who suddenly developed dyspnea despite previously being healthy. Chest computed tomography showed multiple mass-containing cavity lesions, pneumothorax, and pleural effusion in the left thorax. Within 2 weeks, Aspergillus fumigatus grew from his pleural effusion, thus he was diagnosed with Aspergillus empyema. He also developed severe eosinophilia after admission, and was treated with anti-fungal drugs. Although there are many factors that can cause eosinophilia, we suspect that infection with Aspergillus fumigatus was the major cause of the eosinophilia in this patient. The lack of bronchial symptoms and lesions were not consistent with a diagnosis of allergic bronchopulmonary aspergillosis. As far as we know, this is the first case of spontaneous Aspergillus empyema resulting in severe eosinophilia.

A clinicopathological study of surgically resected lung cancer in patients with usual interstitial pneumonia.

BACKGROUND: The clinicopathological characteristics of lung cancer with concomitant usual interstitial pneumonia (UIP) are insufficiently understood. This study aimed to elucidate a characteristic pathological feature of lung cancer that develops in patients with UIP, with a focus on the location of its onset. METHODS: We reviewed surgically obtained specimens, including 547 tumors from 526 patients who underwent lobectomy for lung cancer. Surveyed patients were classified into three groups: patients with UIP (UIP group), patients with lung pathology other than UIP (non-UIP group), and patients without any associated lung pathology (normal group). The histology as well as the lobe and location of the onset of lung cancer were compared among these groups. The peripheral location was subdivided into subpleural, inner and tumor involved centrally secondary to extension. RESULTS: The UIP group comprised 82 patients (male, 71 [87%]; mean age, 71 years; smoking rate, 94%), the non-UIP group comprised 334 patients (male, 267 [80%]; mean age, 69 years; smoking rate, 81%), and the normal group comprised 110 patients (male, 33 [30%]; mean age, 63; smoking rate, 29%). No statistical differences were noted in sex, mean age, or smoking index between the UIP and non-UIP groups. Compared with the non-UIP group, the frequency of squamous cell carcinoma (63% vs. 32%), lower lobe origin (76% vs. 32%), and subpleural location (24% vs. 5%) were significantly higher in the UIP group. CONCLUSIONS: Lung cancers in patients with UIP show a predilection for the subpleural region, where UIP is also thought to originate.

Early-stage diffuse panbronchiolitis in a young patient confirmed by video-assisted lung biopsy: A case report.

A 29-year-old man presented with sputum and cough, which were pointed out by his neighbors. A high-resolution chest computed tomography scan showed well-defined multiple centrilobular nodules and a tree-in-bud pattern. Chest auscultation revealed coarse crackles. He did not report any nasal sinus symptoms. We subsequently performed a video-assisted lung biopsy; the specimen confirmed diffuse panbronchiolitis. Subsequently, sinusitis was confirmed by an otolaryngologist. His symptoms gradually improved following treatment with erythromycin. We report a case of early-stage diffuse panbronchiolitis in a young patient, with multiple intralobular nodules, no bronchiectasis, and a good clinical course.

Multiple, thin-walled cysts are one of the HRCT features of airspace enlargement with fibrosis.

PURPOSE: Airspace enlargement with fibrosis (AEF) has been identified pathologically as a smoking related change. We sought to identify the HRCT findings of AEF and search for distinguishing features from honeycombing. MATERIALS AND METHODS: 50 patients (47 males; mean age 69) were evaluated. All had undergone lobectomy for lung cancer and had confirmed AEF and/or usual interstitial pneumonia (UIP) by pathological evaluation. HRCT findings were first evaluated preresection for resected lobes, and then correlated with the subsequent pathological findings in the resection specimens. Three groups were devised: one with AEF alone to determine the HRCT findings of AEF, a second with AEF and UIP and third with UIP alone. HRCT features of AEF and honeycombing were compared. RESULTS: There were 11 patients (10 male; mean age 69) with AEF alone, 24 patients (22 male; mean age 69) with AEF and UIP, and 15 patients (15 male; mean age 68) with UIP alone. The HRCT on the AEF alone showed subpleural (but not abutting the pleura) multiple thin-walled cysts (MTWCs) in 7 and reticular opacities in 3. The HRCT in AEF and UIP showed MTWCs in 10, reticular opacities in 17; and honeycombing in 5. Among these 35 patients with the pathological finding of AEF (with or without UIP), 17 showed MTWCs. The maximum cyst wall thickness of MTWCs (mean 0.81 mm) was significantly thinner than that of honeycombing (mean 1.56 mm). MTWCs did not locate in lung base and was distant from the pleura. HRCT findings correlated with gross findings on both cysts and honeycombing. No MTWCs were seen in the 15 patients with UIP, 8 of 15 had honeycombing on CT. CONCLUSIONS: We confirmed that HRCT features of AEF were MTWCs and/or reticular opacities. MTWCs might be distinguished from those of honeycomb change. While we prefer the term MTWCs, these sorts of changes have probably been confused with/interpreted as honeycombing and/or empysema in the past.

In vitro oocyte culture and somatic cell nuclear transfer used to produce a live-born cloned goat.

The use of an in vitro culture system was examined for production of somatic cells suitable for nuclear transfer in the goat. Goat cumulus-oocyte complexes were incubated in tissue culture medium TCM-199 supplemented with 10% fetal bovine serum (FBS) for 20 h. In vitro matured (IVM) oocytes were enucleated and used as karyoplast recipients. Donor cells obtained from the anterior pituitary of an adult male were introduced into the perivitelline space of enucleated IVM oocytes and fused by an electrical pulse. Reconstituted oocytes were cultured in chemically defined medium for 9 days. Two hundred and twenty-eight oocytes (70%) were fused with donor cells. After in vitro culture, seven somatic cell nuclear transfer (SCNT) oocytes (3%) developed to the blastocyst stage. SCNT embryos were transferred to the oviducts of recipient females (four 8-cell embryos per female) or uterine horn (two blastocysts per female). One male clone (NT1) was produced at day 153 from an SCNT blastocyst and died 16 days after birth. This study demonstrates that nuclear transferred goat oocytes produced using an in vitro culture system could develop to term and that donor anterior pituitary cells have the developmental potential to produce term offspring. In this study, it suggested that the artificial control of endocrine system in domestic animal might become possible by the genetic modification to anterior pituitary cells.

[A case of constrictive bronchiolitis].

A 31-year-old woman was admitted to our hospital because of a dry cough and progressive exertional dyspnea after her second delivery. She had almost normal laboratory data except for an elevated value for antibody for nucleic acid, and her chest radiograph was normal. However, pulmonary function tests revealed a mixed pattern of dysfunction, and chest CT revealed a mosaic perfusion pattern. The VATS lung biopsy demonstrated complete occlusion of the membranous bronchiole. These results led to a diagnosis of constrictive bronchiolitis (CB). The patient and her family rejected the option of lung transplantation, and selected immunosuppressive therapy (steroid pulse therapy and cyclophosphamide pulse therapy). Her condition improved temporarily, but her respiratory condition worsened progressively, and finally she died one and a half years after the appearance of the symptoms. Although steroid pulse therapy and cyclophosphamide pulse therapy failed to cure the CB, they did retard its progression.

Rapidly progressive respiratory failure in mixed connective tissue disease: report of an autopsy case.

A 64-year-old woman presented with exertional dyspnea. The case was diagnosed as mixed connective tissue disease (MCTD) due to presence of swollen fingers, Raynaud's phenomenon, muscle weakness, positive anti-U1RNP antibody, pericarditis and interstitial pneumonia. Although the histology from a transbronchial lung biopsy (TBLB) indicated organizing pneumonia, corticosteroid therapy was postponed for two months at the patient's request. She died 8 weeks later from acute progressive interstitial pneumonia in spite of the administration of intravenous cyclophosphamide combined with prednisolone. The autopsy revealed exudative and organizing diffuse alveolar damage (DAD). Previous reports have shown that DAD is an extremely rare pulmonary complication in MCTD. This report presents a case of MCTD with acute respiratory failure. This case thus suggests that this therapy should be administered as soon as possible.

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma in Sjögren's syndrome showing only the LIP pattern radiologically.

A 49-year-old woman with a 20-year history of Sjögren's syndrome (SS) was incidentally found to have an abnormal chest X-ray along with dyspnea and desaturation. Chest CT findings showed multiple cystic shadows, ground glass opacity, and small nodule-like lymphocytic interstitial pneumonia (LIP), which have been previously reported. She was diagnosed by surgical lung biopsy to have mucosa-associated lymphoid tissue (MALT) lymphoma. It was difficult to detect the presence of lymphoma by the use of only CT findings. Pulmonary involvement of SS occurs in various forms so that SS patients with pulmonary involvement should undergo open biopsy to reach a definitive diagnosis.

Kinase-driven pathways of EGFR in lung carcinomas: perspectives on targeting therapy.

Despite remarkable advances in oncology medicine, the prognosis of lung cancer patients has not greatly improved over the past few decades. To overcome the current limit, new classes of agents that specifically target particular cascades have been developed. Gefitinib and erlotinib, which are tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR), have provided hope for better survival. The relationship between the sensitivity to gefitinib and the tumors' EGFR mutations have allowed the selective and accelerated use of these therapies. However, their efficacy is still limited, predominantly due to side effects and drug resistance. Further development of rational clinical strategies will require greater clarification of the key signaling factors downstream of EGFR which are potential targets for cancer therapies. In this review, we describe the various observed abnormalities in EGFR, the mechanisms of activation of several critical signaling cascades in lung cancer. Summarizing the data gleaned from preclinical, and clinicopathological aspects, we discuss the molecular mechanisms that may underlie a possible successful response to the blockade of EGFR and/or its downstream signaling.

Mammalian target of rapamycin: a central node of complex signaling cascades.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth and metabolism in response to diverse external stimuli. In the presence of mitogenic stimuli, mTOR transduces signals that activate the translational machinery and promote cell growth. mTOR functions as a central node in a complex net of signaling pathways that are involved both in normal physiological, as well as pathogenic events. mTOR signaling occurs in concert with upstream Akt and tuberous sclerosis complex (TSC) and several downstream effectors. During the past few decades, the mTOR-mediated pathway has been shown to promote tumorigenesis through the coordinated phosphorylation of proteins that directly regulate cell-cycle progression and metabolism, as well as transcription factors that regulate the expression of genes involved in the oncogenic processes. The importance of mTOR signaling in oncology is now widely accepted, and agents that selectively target mTOR have been developed as anti-cancer drugs. In this review, we highlight the past research on mTOR, including clinical and pathological analyses, and describe its molecular mechanisms of signaling, and its roles in the physiology and pathology of human diseases, particularly, lung carcinomas. We also discuss strategies that might lead to more effective clinical treatments of several diseases by targeting mTOR.