Clinical application of ghrelin for chronic respiratory failure.

Chronic respiratory failure, which is often caused by chronic obstructive pulmonary disease, chronic lower respiratory tract infection, or interstitial pneumonia, often leads to cachexia with disease progression. Patients who have chronic respiratory failure with cachexia exhibit increased morbidity. Although cachectic status is an important clinical problem, there are no effective therapies for cachexia. Ghrelin has various effects, including increasing food intake, attenuating sympathetic nerve activity, inhibiting inflammation, increasing cardiac output, and controlling fat utilization. These effects of ghrelin are ideal targets for the treatment of severely wasting chronic respiratory disease. In a few clinical studies, including a small randomized controlled trial, ghrelin administration to cachectic patients with chronic respiratory failure improved exercise tolerance, dyspnea, and appetite. The patients in these studies gained muscle mass and weight. In another study of chronic lower respiratory tract infection with cachexia, ghrelin suppressed airway inflammation by decreasing neutrophil accumulation in the airway, resulting in improvements in oxygenation and exercise tolerance. Although further clinical investigations are needed to clarify its usefulness, ghrelin is expected to become a novel therapy for cachectic patients with chronic respiratory failure.

Epithelial Pten controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity.

RATIONALE: Injury to alveolar epithelial cells (AECs) and to their repair process is integral to the pathogenesis of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF). The mechanisms regulating the integrity of AECs and their intrinsic regulators remain unclear. Pten is a tumor suppressor, and its function in epithelial cells during organ fibrosis is unknown. OBJECTIVES: To determine the role of epithelial Pten in ALI and lung fibrosis. METHODS: Bronchioalveolar epithelium-specific Pten-deleted SP-C-rtTA/(tetO)(7)-Cre/Pten(Δ/Δ) (SOPten(Δ/Δ)) mice were studied by structural, biochemical, and physiologic analyses and compared with wild-type mice. Further mechanistic studies were performed in vivo, in vitro, and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: SOPten(Δ/Δ) mice demonstrated exacerbated alveolar flooding and subsequent augmented lung scarring with enhanced disassembly of tight junctions (TJs) of AECs and degradation of basement membranes. The induction of dominant negative PTEN gene in lung epithelial cells led to augmented transforming growth factor-1-induced disruptions of TJs. Epithelial-derived myofibroblasts were increased in the epithelium-specific Pten-deficient mice. The lungs of bleomycin-treated SOPten(Δ/Δ) mice showed increased pAkt, pS6K, Snail, and matrix metalloproteinase expressions and decreased claudin-4, E-cadherin, and laminin-ß1 expressions. Akt inactivation definitively saved SOPten(Δ/Δ) mice through amelioration of ALI and retention of AEC integrity. We detected a reduction of PTEN expression and AKT hyperactivation in the AECs of human IPF lungs. CONCLUSIONS: Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.

[A case of pulmonary epithelioid hemangioendothelioma that required differentiation from malignant mesothelioma].

A 77-year-old woman presented with a 3-month history of right chest pain and a low-grade fever. Right pleural effusion had been detected at another hospital. Her chest CT scan revealed right pleural effusion, right pleural thickening, and bilateral multiple lung nodules. No specific findings were obtained from an examination of the pleural effusion. Thoracoscopic pleural and lung biopsies were conducted. Histologically, the tumor had an infiltrative growth pattern in the fibrously-thickened parietal pleura, visceral pleura, and lung parenchyma. The tumor was composed of epithelioid and spindle cells, and in some sections, the tumor cells had intracytoplasmic vacuoles, and had formed an immature vascular lumen. Proliferation in a papillary fashion in the alveolar spaces and vascular involvement of tumor were also seen. Immunohistochemically, the tumor cells were positive for factor VIII-related antigen, CD31, and CD34, and negative for calretinin and WT-1. The tumor was therefore diagnosed as pulmonary epithelioid hemangioendothelioma (PEH), which is a rare, low-to-moderate grade vascular tumor of the lung. This disease should be included in the differential diagnosis together with malignant pleural mesothelioma, in cases demonstrating unusual pleural thickening.

[Case of multiple pulmonary arteriovenous fistulas detected during treatment for severe pneumonia].

A 55-year-old woman who developed severe hypoxemia associated with severe pneumonia was admitted to our hospital for mechanical ventilation. She was treated with antibiotics under a diagnosis of mycoplasma pneumonia. Although most clinical findings improved, hypoxemia remained. As a chest CT film showed multiple nodules and an enhanced CT film revealed arterial filling in the nodules, multiple pulmonary arteriovenous fistulas (PAVFs) were considered to be an underlying cause of hypoxemia. Transcatheter coil embolization for 5 PAVFs, significantly ameliorated hypoxemia in the patient. PAVF is a congenital desease, and in many cases, is asymptomatic. Therefore, it was rare for PAVFs to be detected in a middle-aged patient with prolonged hypoxemia associated with pneumonia.

[A case of Westermani Paragonimiasis with atypical change of CT findings].

A 47-year-old man presented with bloody sputum and a cavitary mass shadow was formed in his right middle lobe. Transbronchial lung biopsy revealed the presence of parasite eggs and eosinophil infiltration. Based on the positive reaction against Westermani Paragonimus by multiple dot ELISA, Westermani Paragonimiasis was diagnosed. The cavitary mass shadow disappeared after the treatment with Pragiquantel. This is a rare case of Westermani Paragonimiasis showing interesting changes of chest CT findings during its clinical course.

[A case of Aspergillus brain abscess presenting angular gyrus syndrome].

A 45-year-old man had been treated for chronic alcoholism and he had fever in September 2000. He was diagnosed as lung aspergillosis from chest X-ray findings, leukocytosis, elevated CRP, and beta-D-glucan. Administration of fluconazole was started and his lung lesion subsided. But, generalized clonic tonic convulsion developed and the brain abscess in the left parietal lobe was found by CT. Therefore we made the diagnosis of brain abscess followed by lung aspergillosis. He also showed angular gyrus syndrome. Its capsule was thick and localized in the left parietal lobe. The patient had the surgical resection in August, 2001. Aspergillus hyphae and infiltration of inflammatory cells were seen in the brain sample, therefore the diagnosis of aspergillosis brain abscess was established. Angular gyrus syndrome was ameliorated after the operation.

[Farmer's lung cases of a farmer and his son with high BAL fluid beta-D glucan levels].

A farmer and his son, who treated straw in a cowshed, were admitted to our hospital because of severe dyspnea during summer time. Their chest X-ray films revealed bilateral reticulonodular shadows in the middle to lower lung fields. Bronchoalveolar lavage (BAL) fluid analyses showed a high proportion of lymphocytes and an increased CD4/8 ratio. They were diagnosed with farmer's lung and treated with pulse therapy with methylprednisolone and tapering of steroid. Hypoxemia and interstitial shadow improved, though the farmer relapsed one day after getting home. Immune precipitation showed positive reactions against Aspergillus fumigatus, Aspergillus terreus and Nocardiopsis alba. Their beta D-glucan levels in BAL fluid were higher than those of healthy normal volunteers, whereas their beta D-glucan levels in serum were below the detection levels. Ventilation of the cowshed and wearing a mask should prevent recurrence of the disease.

Ghrelin ameliorates bleomycin-induced acute lung injury by protecting alveolar epithelial cells and suppressing lung inflammation.

Acute lung injury is a critical illness syndrome consisting of acute respiratory failure with bilateral pulmonary infiltrates that is refractory to current therapies. Acute lung injury is characterized by injury of the alveolar capillary barrier, neutrophil accumulation, and induction of pro-inflammatory cytokines followed by devastating lung fibrosis. Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation, and promotes cell survival. We investigated the pharmacological potential of ghrelin in the treatment of acute lung injury by using a bleomycin-induced acute lung injury model in mice. Ghrelin or saline was given to mice daily starting 1 day after bleomycin administration. Ghrelin-treated mice showed a definitively higher survival rate than saline-treated ones. They also had smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of pro-inflammatory cytokines, and subsequent lung fibrosis were notable in ghrelin-treated mice. Additionally, ghrelin administration reduced the injury-induced apoptosis of alveolar epithelial cells. Our results indicate that ghrelin administration exerts a protective effect against acute lung injury by protecting the alveolar epithelial cells and regulating lung inflammation, and highlight ghrelin as a promising therapeutic agent for the management of this intractable disease.