Prediction of requirement for mechanical ventilation in community-acquired pneumonia with acute respiratory failure: a multicenter prospective study.

BACKGROUND: Several severity scoring systems for predicting mortality are established in community-acquired pneumonia (CAP). OBJECTIVES: The predictability of the aggravation such as requirement for mechanical ventilation in addition to mortality was examined in CAP patients with acute respiratory failure by using the age, dehydration, respiratory failure, orientation disturbance and blood pressure (A-DROP) scoring system which was proposed by the Japanese Respiratory Society. METHODS: This study was a prospective, multicenter, observational cohort study. The severity of pneumonia was examined using A-DROP and Pneumonia Severity Index (PSI) which originated from the Infectious Disease Society of America. Requirement for mechanical ventilation and mortality were evaluated for 28 days. RESULTS: 482 CAP patients with acute respiratory failure were enrolled in the study. The 28-day mortality and mechanical ventilation rates were 12.3 and 14.4%, respectively. There were no significant differences in the areas under the receiver-operator characteristic curves for prediction of mortality between A-DROP and PSI (χ² test; p = 0.3613). In the subgroup analyses by severity, the A-DROP scoring system showed a severity-dependent increase of mortality (moderate 5.6%, severe 16.1%, extremely severe 27.1%, Cochran-Armitage trend test; p < 0.0001). Similar results were obtained for mechanical ventilation rate (moderate 9.8%, severe 16.7%, extremely severe 25.4%, Cochran-Armitage trend test; p = 0.0006). The compliance with scoring the A-DROP was higher than that with scoring the PSI (96.9 vs. 71.6%). CONCLUSIONS: The results of this study suggest that the A-DROP scoring system could be a simple CAP risk scoring system which could predict not only mortality, but also the requirement for mechanical ventilation.

Induction of mucin and MUC5AC expression by the protease activity of Aspergillus fumigatus in airway epithelial cells.

Allergic bronchopulmonary mycosis, characterized by excessive mucus secretion, airflow limitation, bronchiectasis, and peripheral blood eosinophilia, is predominantly caused by a fungal pathogen, Aspergillus fumigatus. Using DNA microarray analysis of NCI-H292 cells, a human bronchial epithelial cell line, stimulated with fungal extracts from A. fumigatus, Alternaria alternata, or Penicillium notatum, we identified a mucin-related MUC5AC as one of the genes, the expression of which was selectively induced by A. fumigatus. Quantitative RT-PCR, ELISA, and histochemical analyses confirmed an induction of mucin and MUC5AC expression by A. fumigatus extracts or the culture supernatant of live microorganisms in NCI-H292 cells and primary cultures of airway epithelial cells. The expression of MUC5AC induced by A. fumigatus extracts diminished in the presence of neutralizing Abs or of inhibitors of the epidermal growth factor receptor or its ligand, TGF-α. We also found that A. fumigatus extracts activated the TNF-α-converting enzyme (TACE), critical for the cleavage of membrane-bound pro-TGF-α, and its inhibition with low-molecular weight inhibitors or small interfering RNA suppressed the expression of MUC5AC. The protease activity of A. fumigatus extracts was greater than that of other fungal extracts, and treatment with a serine protease inhibitor, but not with a cysteine protease inhibitor, eliminated its ability to activate TACE or induce the expression of MUC5AC mRNA in NCI-H292. In conclusion, the prominent serine protease activity of A. fumigatus, which caused the overproduction of mucus by the bronchial epithelium via the activation of the TACE/TGF-α/epidermal growth factor receptor pathway, may be a pathogenetic mechanism of allergic bronchopulmonary mycosis.

Gradual increase of high mobility group protein b1 in the lungs after the onset of acute exacerbation of idiopathic pulmonary fibrosis.

The pathogenesis of acute exacerbation of idiopathic pulmonary fibrosis (IPF) remains to be elucidated. To evaluate the roles of inflammatory mediators in acute exacerbation, the concentrations of high mobility group protein B1 (HMGB1), a chief mediator of acute lung injury, and 18 inflammatory cytokines were measured in the bronchoalveolar lavage fluid, serially sampled from seven IPF patients after the onset of acute exacerbation. HMGB1 gradually increased in the alveolar fluid after the onset of acute exacerbation, in positive correlation with monocytes chemotactic protein-1 (MCP-1), a potent fibrogenic mediator. In the lung tissues of eight IPF patients autopsied after acute exacerbation, intense cytoplasmic staining for HMGB1 was observed in the alveolar epithelial cells in alveolar capillary augmented lesions, where the capillary endothelial cells remarkably reduced the expression of thrombomodulin, an intrinsic antagonist of HMGB1. These results suggest pathogenic roles for HMGB1 and MCP-1 in the late phase of acute exacerbation of IPF.

Reevaluation of the efficacy and safety of the neutrophil elastase inhibitor, Sivelestat, for the treatment of acute lung injury associated with systemic inflammatory response syndrome; a phase IV study.

INTRODUCTION: Sivelestat, a neutrophil elastase inhibitor, has been approved in Japan for the treatment of patients with acute lung injury (ALI) associated with systemic inflammatory response syndrome (SIRS). The Pharmaceuticals and Medical Devices Agency (PMDA) has ordered to conduct a postmarket clinical study in order to reevaluate the efficacy and safety of Sivelestat in actual clinical settings in Japan. METHODS: According to the PMDA's order, we evaluated the efficacy and safety of Sivelestat in Japanese patients with ALI associated with SIRS using ventilator-free days (VFD) as the primary endpoint. The surrogate endpoints are ventilator-weaning rate, ICU discharge rate, and 180-day survival rate. Study design was an open-label, non-randomized, multi-center clinical trial. Sivelestat was intravenously administered at 0.2 mg/kg/h continuously for a maximum of 14 days. Sivelestat group and control group were compared by adjusting the outcome values using an inverse probability of treatment weighted method based on the propensity scores. RESULTS: Four hundred and four Sivelestat group patients and 177 control group patients were enrolled. The adjusted mean number of VFD was 15.7 and 12.1 in the Sivelestat group and control group, respectively (P = 0.0022). Both the adjusted ventilator-weaning rate and ICU discharge rate were significantly higher in the Sivelestat group than in the control group (P = 0.0028 and P = 0.019, respectively). The adjusted 180-day survival rate was significantly higher in the Sivelestat group than in the control group (71.8 percent vs. 56.3 percent). CONCLUSIONS: Sivelestat contributed to early weaning from the mechanical ventilation, while showing no negative effect on the long-term outcomes of ALI associated with SIRS. The results of this study suggest the clinical usefulness of Sivelestat in this patient population.

Carbon black nanoparticles enhance bleomycin-induced lung inflammatory and fibrotic changes in mice.

With the recent increasing use of nanoparticles, there is concern that they may become an environmental risk factor as airborne particles. However, the impact of these particles on susceptible subjects with predisposing lung disease have not been sufficiently elucidated. In the present study, we investigated the effects of nanoparticles on pulmonary inflammatory and fibrotic changes induced by intratracheal bleomycin (BLM) challenge in mice. Mice were intratracheally administered either vehicle, 14-nm carbon black nanoparticles (CBNPs), BLM or BLM plus CBNP. First, we assessed lung collagen content, lung compliance and fibrotic changes in histopathology on day 21 after instillation. Then, to elucidate how CBNP contributes to the development of BLM-induced fibrosis, we collected bronchoalveolar lavage (BAL) fluid on days 2, 7, 14 and 21 and determined the total and differential cell counts and concentrations of two proinflammatory cytokines (keratinocyte chemoattractant [KC] and interleukin [IL]-6) and two fibrogenic mediators (CC chemokine ligand 2 [CCL2] and transforming growth factor-ß(1) [TGF-ß(1)]). Expression of nitrotyrosine, an indicator of oxidant injury, was also evaluated on days 7 and 21. CBNP, when combined with BLM, significantly enhanced BLM-induced increase in lung collagen content, decrease in lung compliance, and fibrotic changes in histopathology. CBNP significantly augmented BLM-induced increase in the numbers of inflammatory cells in BAL fluid on days 2 and 7 and levels of KC and IL-6 on day 2. In addition, CBNP administered in combination with BLM significantly elevated the levels of CCL2 on days 2, 7 and 14, and TGF-ß(1) on day 14 in BAL fluid as compared with BLM alone. Nitrotyrosine expression was also increased by BLM plus CBNP compared with BLM alone. In contrast, CBNP did not exert any significant effect on these parameters by itself. These results indicate that CBNP can exaggerate BLM-induced inflammatory and fibrotic changes in the lung, suggesting the potential impact of nanoparticles on lung inflammation and fibrosis.

Impact of serum high-mobility group box 1 protein elevation on oxygenation impairment after thoracic aortic aneurysm repair.

High-mobility group box 1 protein (HMGB1) is a late mediator of inflammatory responses that can cause acute lung injury. We examined the significance of serum HMGB1 elevation in the development of systemic inflammatory response syndrome (SIRS) and lung oxygenation impairment (LOI) after thoracic aortic aneurysm (TAA) repair. Serial measurements of the serum HMGB1 level and SIRS score for 7 days after surgery were determined in 20 patients with TAA who underwent surgical repair. Arterial oxygen tension was measured serially for at least 4 days after surgery, and LOI was defined as the lowest PaO(2)/FiO(2) ratio ≤ 200 mmHg. The serum HMGB1 level was markedly increased after surgery, peaking on day 2, and remained significantly elevated on day 7. Peak HMGB1 level positively correlated with SIRS duration and the cumulative SIRS score during postoperative days 1-7 (P = 0.0013 and P = 0.0004, respectively). Peak HMGB1 level and cumulative SIRS score were higher in patients with LOI than in those without (P = 0.01 and P = 0.044, respectively). Peak HMGB1 level was negatively correlated with the lowest PaO(2)/FiO(2) ratio (P = 0.0077) and positively correlated with postoperative length of hospitalization (P = 0.042). A greater serum HMGB1 elevation after TAA repair was associated with more severe SIRS and a higher incidence of LOI. HMGB1 might play a key role in the pathogenesis of SIRS and LOI after surgical TAA repair.

Bronchoscopic microsampling is a useful complementary diagnostic tool for detecting lung cancer.

PURPOSE: Bronchoscopic microsampling (BMS) is a novel and direct method with which to obtain epithelial lining fluid (ELF) from the lungs. Analysis of DNA hypermethylation of tumor suppressor genes (TSGs) is expected to be a sensitive tool for the early detection of lung cancer. It has been reported that the existence of EGFR mutations and EML4-ALK gene rearrangements are related to the sensitivity of corresponding kinase inhibitors. We aimed to evaluate the suitability of ELF as a sample for analyzing molecular changes specific for lung cancer. PATIENTS AND METHODS: We collected ELF from 61 lung cancer patients by BMS from the airway close to the peripheral lung nodule and purified the nucleic acids. We performed methylation specific PCR in each ELF as well as matched serum and tumor tissue for TSGs for DNA methylation analysis. We also examined EGFR mutations and EML4-ALK rearrangement. RESULTS: The sensitivity for detecting DNA hypermethylation in ELF vs serum was 74.1% vs 18.5%. We found 60.1% of patients had at least one hypermethylation in ELF, while only 27.9% had it in serum. Of note, DNA hypermethylation was detected even in stage I patients (60.0%) and the detection rate was almost the same level in each stage. We also found the sensitivity for detecting EGFR mutation in ELF vs serum was 58.3% vs 8.3%. We detected an EML4-ALK fusion gene using ELF in one patient. CONCLUSIONS: BMS is an alternative method to detect cancer specific genetic and epigenetic alterations and will be a useful complementary diagnostic tool for lung cancer. SUMMARY: Investigation of genetic and epigenetic changes associated with lung cancer has clinical importance for its diagnosis and management. The clinical usefulness of bronchoscopic microsampling (BMS) in lung cancer has not yet been evaluated. This study demonstrates that BMS could be useful for detecting lung cancer specific molecular changes and valuable for early diagnosis and determination of treatment options for lung cancer.

Distinct epigenetic regulation of tumor suppressor genes in putative cancer stem cells of solid tumors.

Epigenetic gene regulation plays essential roles in differentiation of embryonic and tissue stem cells. In these benign undifferentiated cells, some polycomb targeted genes are kept in a state of DNA hypomethylation and they have a distinct chromatin signature termed bivalent chromatin structure to maintain their plasticity. We hypothesized that cancer stem cells (CSC), the malignant counterpart of these cells, are also under the control of epigenetics like benign stem cells. We compared the DNA methylation and chromatin structure in 10 tumor suppressor genes between CSC and differentiated cancer cells of MCF7 and Huh7 cells. We found that the level of DNA methylation was indeed significantly lower in CSC, while surprisingly, the bivalent chromatin structure was more ubiquitously seen in differentiated cancer cells compared to CSC. However, repressive marks of chromatin structure, namely H3K27me3 and EZH2, were significantly lower in CSC. As a consequence, CSC remained in a higher transcriptionally active chromatin state compared to differentiated cancer cells. We found that the differentiation of CSCs is also epigenetically regulated. These findings could help towards a comprehensive understanding of CSC, and also improve the development of eradicative therapies against human malignancies.

Evaluation of pathogen detection from clinical samples by real-time polymerase chain reaction using a sepsis pathogen DNA detection kit.

INTRODUCTION: Sepsis is a serious medical condition that requires rapidly administered, appropriate antibiotic treatment. Conventional methods take three or more days for final pathogen identification and antimicrobial susceptibility testing. We organized a prospective observational multicenter study in three study sites to evaluate the diagnostic accuracy and potential clinical utility of the SeptiFast system, a multiplex pathogen detection system used in the clinical setting to support early diagnosis of bloodstream infections. METHODS: A total of 212 patients, suspected of having systemic inflammatory response syndrome (SIRS) caused by bacterial or fungal infection, were enrolled in the study. From these patients, 407 blood samples were taken and blood culture analysis was performed to identify pathogens. Whole blood was also collected for DNA Detection Kit analysis immediately after its collection for blood culture. The results of the DNA Detection Kit, blood culture and other culture tests were compared. The chosen antimicrobial treatment in patients whose samples tested positive in the DNA Detection Kit and/or blood culture analysis was examined to evaluate the effect of concomitant antibiotic exposure on the results of these analyses. RESULTS: SeptiFast analysis gave a positive result for 55 samples, while 43 samples were positive in blood culture analysis. The DNA Detection Kit identified a pathogen in 11.3% (45/400) of the samples, compared to 8.0% (32/400) by blood culture analysis. Twenty-three pathogens were detected by SeptiFast only; conversely, this system missed five episodes of clinically significant bacteremia (Methicillin-resistant Staphylococcus aureus (MRSA), 2; Pseudomonas aeruginosa, 1; Klebsiella spp, 1; Enterococcus faecium, 1). The number of samples that tested positive was significantly increased by combining the result of the blood culture analysis with those of the DNA Detection Kit analysis (P = 0.01). Among antibiotic pre-treated patients (prevalence, 72%), SeptiFast analysis detected more bacteria/fungi, and was less influenced by antibiotic exposure, compared with blood culture analysis (P = 0.02). CONCLUSIONS: This rapid multiplex pathogen detection system complemented traditional culture-based methods and offered some added diagnostic value for the timely detection of causative pathogens, particularly in antibiotic pre-treated patients. Adequately designed intervention studies are needed to prove its clinical effectiveness in improving appropriate antibiotic selection and patient outcomes.

Production and activation of matrix metalloproteinase 7 (matrilysin 1) in the lungs of patients with idiopathic pulmonary fibrosis.

CONTEXT: Idiopathic pulmonary fibrosis (IPF) is characterized by diffuse interstitial inflammation and fibroblast proliferation with accelerated remodeling of extracellular matrix, which result in irreversible destruction of the lung's architecture. OBJECTIVE: To elucidate the production levels, tissue localization, and activation of matrix metalloproteinase 7 (MMP-7) in the lungs of patients with IPF. DESIGN: Bronchoalveolar lavage analysis was performed in 17 IPF patients and 6 healthy volunteers. Levels of MMP-7 in blood were assayed in 23 IPF patients and 20 controls. Histologic and immunohistochemical analyses were performed on paraffin sections of the lung tissues from patients with IPF, interstitial pneumonia associated with rheumatoid arthritis, or nonspecific interstitial pneumonia. RESULTS: The proMMP-7 levels in bronchoalveolar lavage fluids from IPF patients were significantly higher than those from healthy controls, although there was no difference in the serum levels between the 2 groups. By immunohistochemistry, proMMP-7 was localized mainly to the hyperplastic alveolar and metaplastic bronchiolar epithelial cells in the lung tissues from IPF patients. Active MMP-7 was immunolocalized on alveolar macrophages and hyperplastic epithelial cells, which were also immunostained with antibody against CD151, a molecule associated with activation of proMMP-7. Immunoblot analysis indicated the overproduction of proMMP-7 together with a small amount of active MMP-7 in bronchoalveolar lavage fluids from IPF patients. The MMP-7 activity was detected in a cross-linked carboxymethylated transferrin film assay. CONCLUSIONS: proMMP-7 is excessively produced by hyperplastic alveolar and metaplastic bronchiolar epithelial cells and activated locally in the lungs of IPF patients, suggesting that MMP-7 may contribute to the pathology of IPF.

Role of interleukin-6 in elastase-induced lung inflammatory changes in mice.

Interleukin-6 (IL-6) is known to be involved in the pathogenesis of various inflammatory diseases, but its role in the development of pulmonary emphysema remains unclear. Wild-type (WT) and IL-6-deficient mice received either phosphate-buffered saline (PBS) or porcine pancreatic elastase (PPE) intratracheally. The development of emphysema was determined by measuring the mean linear intercept (Lm). The lung specimens were also subjected to immunohistochemistry for single-stranded DNA to detect apoptotic cells. Lung mechanics and airway responsiveness to inhaled methacholine were analyzed. Bronchoalveolar lavage (BAL) fluid was subjected to evaluation of inflammatory cell accumulation and cytokine measurement. PPE treatment caused significant increases in Lm and lung compliance, which was attenuated by IL-6 deficiency. The increases in apoptotic cells in the lung were attenuated in IL-6 null mice. Airway responsiveness was not affected by PPE challenge or IL-6 deficiency. Intratracheal PPE increased the cell counts in BAL fluid throughout the observation, which was suppressed in IL-6 null mice. In BAL fluid, PPE-induced increases in the levels of macrophage inflammatory protein (MIP)-1alpha and eotaxin were mitigated by IL-6 deficiency. PPE-induced up-regulation of matrix metalloproteinase (MMP)-12 in the lung was attenuated by IL-6 deficiency. These results indicate that IL-6 may play an important role in the development of elastase-induced lung inflammatory changes.

The combination of multiple receptor tyrosine kinase inhibitor and mammalian target of rapamycin inhibitor overcomes erlotinib resistance in lung cancer cell lines through c-Met inhibition.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) show antitumor activity in a subset of non-small cell lung cancer (NSCLC) patients. However, the initial tumor response is followed by recurrence. Several studies have suggested the importance of other receptor tyrosine kinases (RTK) and downstream kinases as potential targets in the treatment of NSCLC. We used the multiple-RTK inhibitor AEE788, which inhibits EGFR, vascular endothelial growth factor receptor, and human epidermal growth factor receptor 2, with and without the downstream kinase inhibitor RAD001 (an inhibitor of mammalian target of rapamycin). AEE788 inhibited cell growth more effectively than did erlotinib in three NSCLC cell lines examined (A549, H1650, and H1975). However, in the EGFR-TKI-resistant cell line H1975 harboring T790M resistance mutation, cell growth inhibition by AEE788 was only mild, and the phosphorylation of its leading targets such as EGFR and vascular endothelial growth factor receptor 2 was not inhibited. In H1975, AEE788 induced significantly greater cell growth inhibition when combined with RAD001 than when used alone. This cooperative effect was not seen with the combination of erlotinib and RAD001. We found that c-Met was highly phosphorylated in this cell line, and the phosphorylated c-Met was inhibited effectively by AEE788. Using a phospho-RTK array, the phosphorylation of c-Met and insulin-like growth factor-I receptor was inhibited by AEE788. These results suggest that upstream RTK inhibitor overcomes the acquired resistance to EGFR-TKI when combined with downstream kinase inhibitor. Thus, the combined inhibition of upstream and downstream RTKs is a promising strategy for the treatment of NSCLC.

Strain-specific phenotypes of airway inflammation and bronchial hyperresponsiveness induced by epicutaneous allergen sensitization in BALB/c and C57BL/6 mice.

BACKGROUND: Allergen sensitization through a disrupted skin barrier appears to play a prominent role in the development of atopic diseases, including allergic asthma. The role of the genetic background in immunological and physiological phenotypes induced by epicutaneous sensitization is undetermined. METHODS: BALB/c and C57BL/6 mice were sensitized either epicutaneously by patch application of ovalbumin (OVA) or systemically by intraperitoneal injection of OVA with alum before exposure to aerosolized OVA. The concentrations of OVA-specific immunoglobulin in serum and cytokines in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay. The severity of airway inflammation was evaluated by cell counts in BALF, and bronchial responsiveness to methacholine was measured by the flexiVent system. RESULTS: The production of OVA-specific IgG1 and IgE was greater in the epicutaneously sensitized BALB/c than C57BL/6 mice. In contrast, both eosinophilic airway inflammation and bronchial responsiveness to methacholine were more prominent in the C57BL/6 than in the BALB/c mice. The concentrations of interleukin-4 increased significantly in the BALF from C57BL/6 mice only. No between-strain differences were observed after intraperitoneal sensitization. CONCLUSIONS: The C57BL/6 mouse is a more appropriate model than the BALB/c mouse to study the relationship between skin barrier dysfunction and the pathogenesis of allergic asthma.

High-mobility-group box chromosomal protein 1 as a new target for modulating stress response.

Major surgical procedures induce a systemic inflammatory response syndrome (SIRS) characterized by the overproduction of proinflammatory cytokines, which induces excessive stress and may trigger postoperative complications. This has prompted the hypothesis that drugs which relieve SIRS might improve the postoperative course of major surgery. One of the most promising targets for these drugs is high-mobility-group box chromosomal protein 1 (HMGB1). In 1999, HMGB1 was found to be a key late mediator of sepsis. It is now known to be associated with various kinds of acute and chronic inflammation, and is recognized as one of the most important danger signals in stress response. In this article, we present the latest information about HMGB1 and discuss its promise as a novel target for modulating stress response.

Association between beta-adrenoceptor gene polymorphisms and relative response to beta 2-agonists and anticholinergic drugs in Japanese asthmatic patients.

BACKGROUND AND OBJECTIVE: Whether beta(2)-adrenoceptor gene (ADRB2) polymorphisms are associated with airway responsiveness to beta(2)-agonist medications remains controversial, partly due to factors that may confound pharmacogenetic associations, including age, cigarette smoking and airway remodelling. To overcome these problems, we performed an analysis using parameters that reflected the specific bronchodilator response to beta(2)-agonists. METHODS: The increases in FEV(1) after inhalation of procaterol hydrochloride (Delta FEV(1) procaterol) or oxitropium bromide (Delta FEV(1) oxitropium), and after sequential inhalation of procaterol and oxitropium (total airway reversibility), were measured in 81 Japanese patients with moderate to severe asthma. Approximately 3 kb of the DNA sequence of the coding and 5'-flanking regions of ADRB2 were genotyped by direct sequencing and PCR-restriction fragment length polymorphism assay. RESULTS: The mean age of the participants was 54 years, and 38 (47%) were smokers. Although Delta FEV(1) procaterol and Delta FEV(1) oxitropium adjusted for predicted FEV(1) were not associated with ADRB2 polymorphisms, the ratio of Delta FEV(1) procaterol to total airway reversibility was significantly associated with the ADRB2 A46G genotype (P < 0.05). Patients who were homozygous for the A46 allele (arginine at amino acid 16) were more responsive than carriers of the G46 (glycine 16) allele (P = 0.008). Multivariate linear regression analysis showed that Delta FEV(1) procaterol was correlated with the number of A46 alleles (P = 0.014), and also with total airway reversibility (P < 0.001) and smoking index in current smokers (P = 0.009). CONCLUSIONS: The ADRB2 A46G polymorphism was associated with a relatively greater bronchodilator responsiveness to beta(2)-agonists even in elderly asthmatic patients and smokers.

Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis.

Little is known about the pathobiology of acute exacerbation of idiopathic pulmonary fibrosis (IPF), a condition that shares clinical and histopathological features with acute lung injury. Plasma biomarkers have been well studied in acute lung injury and have provided insight into the underlying disease mechanism. The objective of this study was to determine the plasma biomarker profile of acute exacerbation of IPF and compare this profile with that of stable IPF and acute lung injury. Plasma was collected from patients with stable IPF, acute exacerbation of IPF, and acute lung injury for measurement of biomarkers of cellular activity/injury (receptor for advanced glycation endproducts, surfactant protein D, KL-6, von Willebrand factor), systemic inflammation (IL-6), and coagulation/fibrinolysis (protein C, thrombomodulin, plasminogen activator inhibitor-1). Plasma from patients with acute exacerbation of IPF showed significant elevations in markers of type II alveolar epithelial cell injury and/or proliferation, endothelial cell injury, and coagulation. This profile differed from the biomarker profile in patients with acute lung injury. These findings support the hypothesis that type II alveolar epithelial cells are centrally involved in the pathobiology of acute exacerbation of IPF. Furthermore, they suggest that acute exacerbation of IPF has a distinct plasma biomarker profile from that of acute lung injury.

Effect of Toll-like receptor 4 inhibitor on LPS-induced lung injury.

OBJECTIVE AND DESIGN: Toll-like receptor 4 (TLR4) plays important roles in the recognition of lipopolysaccharide (LPS) and the activation of inflammatory cascade. In this study, we evaluated the effect of TAK-242, a selective TLR4 signal transduction inhibitor, on acute lung injury (ALI). MATERIALS AND METHODS: C57BL/6J mice were intravenously treated with TAK-242 15 min before the intratracheal administration of LPS or Pam3CSK4, a synthetic lipopeptide. Six hours after the challenge, bronchoalveolar lavage fluid was obtained for a differential cell count and the measurement of cytokine and myeloperoxidase levels. Lung permeability and nuclear factor-kappaB (NF-kappaB) DNA binding activity were also evaluated. RESULTS: TAK-242 effectively attenuated the neutrophil accumulation and activation in the lungs, the increase in lung permeability, production of inflammatory mediators, and NF-kappaB DNA-binding activity induced by the LPS challenge. In contrast, TAK-242 did not suppress inflammatory changes induced by Pam3CSK4. CONCLUSION: TAK-242 may be a promising therapeutic agent for ALI, especially injuries associated with pneumonia caused by Gram-negative bacteria.

[A case of miliary tuberculosis showing acute respiratory distress syndrome in rheumatoid arthritis].

A 62-year-old man, treated with corticosteroids and immunosuppressants for rheumatoid arthritis, visited hospital with high fever and dyspnea on exertion. A CT scan of the chest demonstrated bilateral diffuse ground glass opacities. On the basis of the findings of the CT scan, he was initially given a diagnosis of interstitial pneumonia. He was then referred to our hospital and admitted to the intensive care unit (ICU), where because of progressive respiratory failure, he was put on mechanical ventilation. A bronchoscopy specimen after intubation turned out to be positive for acid-fast bacilli, which were confirmed to be mycobacterium tuberculosis by a polymerase chain reaction test. He was given a diagnosis of miliary tuberculosis complicated with acute respiratory distress syndrome (ARDS). He died of respiratory failure despite treatment with antituberculosis drugs. The autopsy revealed necrotizing epithelioid granulomas in both lungs, mediastinal lymph nodes, the liver, both kidneys, vertebrae and other organs. Diffuse alveolar damage was also found in both lungs. It is often difficult to detect disseminated nodules in the miliary tuberculosis with ARDS. Miliary tuberculosis should be suspected in patients in an immunosuppressant state with rheumatoid arthritis, and who have respiratory symptoms or fever of unknown origin.

Acute respiratory distress syndrome after percutaneous cryotherapy for a pulmonary metastatic lesion.

Percutaneous cryotherapy (PCT) under computed tomographic guidance is minimally invasive, with satisfactory local control of primary lung cancer and pulmonary metastatic lesions. We report a case of acute respiratory distress syndrome (ARDS) in a patient who underwent PCT for lung metastasis of recurrent esophageal cancer. The patient responded to pulse steroid therapy and recovered from severe respiratory failure. Excessive inflammatory response to necrotic debris might contribute to the development of ARDS. To the best of our knowledge, this is the first report describing the details of ARDS following PCT.

[Long-term treatment with a humanized anti-interleukin-6 receptor antibody (tocilizumab), improving interstitial pneumonia in a patient with multicentric Castleman disease].

A 46-year-old man was admitted for the evaluation of a dry cough and dyspnea on exertion. Laboratory tests revealed anemia, elevated CRP, polyclonal hyperimmunoglobulinemia, and an elevated interleukin-6 level. Radiological examination of the chest showed peribronchovascular consolidations, ground glass opacities, small nodular opacities, and interlobular septal thickenings in the lungs, accompanied with hilar and mediastinal lymphadenopathies. A video-assisted thoracoscopic lung and mediastinal lymph node biopsy revealed plasmacytic and lymphocytic infiltration around the bronchovascular bundles of the lungs, and plasmacytic infiltration in the interfollicular areas of the nodes. Based on these findings, a diagnosis of multicentric Castleman disease was confirmed. The patient received a humanized anti-interleukin-6 receptor antibody, (tocilizumab, 8 mg/kg), every 2 weeks for 3 years, during which time, his PaO2 level improved from 64.1 Torr to 83.4 Torr, vital capacity increased from 2.53 L to 3.95 L, and radiological abnormalities in the lungs gradually improved, suggesting that tocilizumab is effective for interstitial pneumonia in patients with multicentric Castleman disease.