Purpose: Interleukin (IL)-25 and IL-33 induce IL-5 production by various types of cells, such as type 2 helper T (Th2) cells and type 2 innate lymphoid cells. The number of Th2 cells and concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) are increased in patients with eosinophilic pneumonia (EP). To examine the contribution of IL-25 and IL-33 to eosinophilic inflammation of the lung in humans, we evaluated IL-5, IL-25 and IL-33 levels in the BALF of patients with EP. Methods: IL-5, IL-25, and IL-33 concentrations in the BALF were measured by enzyme-linked immunosorbent assay in patients with acute eosinophilic pneumonia (AEP), chronic eosinophilic pneumonia (CEP), idiopathic pulmonary fibrosis (IPF), and sarcoidosis. Results: The absolute number of eosinophils, and IL-5 levels, but not IL-33 levels, in the BALF were significantly higher in patients with EP than in patients with IPF and sarcoidosis. IL-25 levels in the BALF were significantly higher in patients with CEP, but not in patients with AEP, than in patients with IPF and sarcoidosis. The absolute number of eosinophils was significantly correlated with the IL-5 concentration in the BALF of patients with EP. IL-5 concentrations were significantly correlated with IL-25 concentrations in the BALF of patients with CEP, but not in patients with AEP. IL-5 levels were not correlated with IL-33 levels in the BALF of patients with EP. Conclusions: Our findings suggest that IL-25 plays an important role via IL-5 in eosinophilic lung inflammation in patients with CEP.
Exploration of the mechanisms of alveolar epithelial cells (AECs) integrity is important for understanding the pathogenesis of acute lung injury. The tight junctions (TJs) of AECs provide intercellular sealing and are integral to the maintenance of the integrity of the alveolar-capillary barrier. However, the mechanisms regulating AEC barrier integrity are not fully understood. We explored the role of epithelial Pten in lung injury by using lung-epithelium specific Pten-deficient (SOPten) mice. We also investigated the function of Pten by using stably introduced lentivirus encoding either wild-type PTEN (lenti-PTEN-WT) or dominant-negative mutant of PTEN (lenti-PTEN-CS) in BEAS-2B. SOPten lungs after bleomycin or lipopolysaccharide injury exhibited extensive intralveolar edema and increased alveolar permeability. SOPten lungs demonstrated loss of TJs morphology and dissociation of cell-cell contacts after injury. Levels of TJs protein were decreased in SOPten lungs after injury. Exogenous expressions of PTEN were observed in the lenti-PTEN-WT and lenti-PTEN-CS transfected cells. Expression of WT PTEN abolished Akt phosphorylation, whereas that of PTEN-CS increased pAkt levels in BEAS-2B cells. After treatment with transforming growth factor (TGF)-beta1, monolayers of the lenti-PTEN-WT cells showed retained transpeithelial electrical resistance (TER) levels compared with those of untreated cells. In contrast, monolayers of the lenti-PTEN-CS cells exhibited a substantial reduction of TER after TGF-beta1 treatment. Levels of TJs protein were severely attenuated in the TGF-beta1-treated lenti-PTEN-CS cells. These findings reveal that epithelial Pten is crucial guardian controlling AECs barrier integrity.
Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction that is associated with an allergic immunological response to Aspergillus species via Th2-related inflammation. The long-term use of a systemic corticosteroid is often needed for the treatment of ABPA. However, systemic corticosteroid treatment imposes a risk of the onset of a nontuberculous mycobacterial infection. Here we report the case of a patient with ABPA who required the long-term use of an oral corticosteroid because her repeated asthmatic attacks were successfully treated with mepolizumab, an anti-interleukin-5 monoclonal antibody. The patient, a 60-year-old Japanese female, had been treated with an oral corticoid and itraconazole. Despite the success of the initial treatment for ABPA, it was difficult to discontinue the use of the oral corticosteroid. In addition, Mycobacterium avium was detected from her bronchial lavage. We initiated mepolizumab treatment to taper the amount of corticosteroid and control the asthma condition. The patient's number of blood eosinophils, serum IgE level, fractional exhaled nitric oxide level, dosage of oral prednisolone, and need for inhaled budesonide/formoterol all improved, without an exacerbation of her asthma attacks. Although further research regarding mepolizumab treatment is needed, we believe that mepolizumab could be considered one of the agents for treating refractory ABPA.
Individual alveolar epithelial cells (AECs) collaboratively form a tight barrier between atmosphere and fluid-filled tissue to enable normal gas exchange. The tight junctions of AECs provide intercellular sealing and are integral to the maintenance of the AEC barrier integrity. Disruption and failure of reconstitution of AEC barrier result in catastrophic consequences, leading to alveolar flooding and subsequent devastating fibrotic scarring. Recent evidences reveal that many of the fibrotic lung diseases involve AECs both as a frequent target of injury and as a driver of ongoing pathological processes. Aberrantly activated AECs express most of the growth factors and chemokines responsible for the proliferation, migration, and activation of fibroblasts. Current evidences suggest that AECs may acquire overdrive activation in the initial step of fibrosis by several mechanisms, including abnormal recapitulation of the developmental pathway, defects of the molecules essential for epithelial integrity, and acceleration of aging-related properties. Among these initial triggering events, epithelial Pten, a multiple phosphatase that negatively regulates the PI3K/Akt pathway and is crucial for lung development, is essential for the prevention of alveolar flooding and lung fibrosis through the regulation of AEC barrier integrity after injury. Reestablishment of AEC barrier integrity also involves the deployment of specialized stem/progenitor cells.
A 74-year-old smoking man was admitted because of lung cancer with metastatic brain tumor. Examinations for lung cancer and brain tumor showed adenocarcinoma (clinical stage IV). Four courses of chemotherapy were not effective. Administration of gefitinib started from June 2003, but was halted after only two months because of skin rash. Lung tumor disappeared on chest computerized tomography in January 2004 and no recurrence has been detected as of March 2006. This is a rare male super-responder to gefitinib.
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor. Findings from the past decade indicate that ghrelin induces a positive energy balance and weight gain by stimulating food intake and adiposity, controlling fat utilization and thermogenesis, increasing cardiac output, and attenuating sympathetic nerve activity. In small studies, repeated ghrelin administration leads to improvements in symptoms, muscle wasting and exercise tolerance in cachectic patients with pulmonary disease. In this randomized, dose-comparison study, 44 weight loosing patients with COPD or IPF or pulmonary tuberculosis sequelae were randomly assigned exercise training with intravenous twice-daily administration of 1 or 2 μg/kg ghrelin for 3 weeks. The primary outcome was improvement in 6-min walking distance (6MWD). The secondary outcome was change in peak VO2. Of the enrolled 44 patients, 35 cases were COPD, 4 cases were IPF and 5 cases were pulmonary tuberculosis sequelae. Twenty-one patients were assigned to the 1 μg/kg ghrelin group and 23 to the 2 μg/kg ghrelin group. Improvements from the pre-intervention 6MWD after the treatment were similar between groups. Mean increases in peak VO2 were significantly greater in the 2 μg/kg group (63.1ml/min) than in the 1 μg/kg group (-63.8ml/min). No treatment-related serious adverse events were reported. Increase in the oxygen uptake capacity was greater in patients receiving 2 μg/kg ghrelin than in those receiving 1 μg/kg. Ghrelin treatment was well tolerated.
