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.

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.

[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.

Infective endocarditis at the tricuspid valve following central venous catheterization.

We report a case of infective endocarditis at the tricuspid valve attributed to central venous catheterization. The patient was a 35-year-old woman who had multiple septic emboli in her lung due to tricuspid valve endocarditis after successful treatment of bronchiolitis obliterans organizing pneumonia. She also had right ileosacral arthritis. The case was closely related to catheter-associated Staphylococcus aureus bacteremia. She was treated with intravenous administration of vancomycin and surgical removal of vegetation and tricuspid valvuloplasty. Since infective endocarditis can be a complication of central venous catheterization with high morbidity and mortality, maximal precautions to minimize the risk, early detection, and appropriate treatment of these complications are mandatory to improve patients' outcome.

[A case of negative pressure pulmonary hemorrhage (NPPH) due to upper airway obstruction induced by asphyxia].

A non-smoking 76-year-old woman was admitted to our hospital complaining of cough, bloodstained sputum and difficulty in breathing that had developed while she was eating a meal. The initial diagnosis was upper airway obstruction. Her past history revealed no major illness, except that she was under medication for the treatment of hypertension. On examination, chest radiography and computed tomography (CT) scans showed diffuse ground glass opacities in both lungs, and bronchoalveolar lavage studies further yielded findings compatible with pulmonary hemorrhage. The patient's symptoms and hypoxemia improved gradually without any specific treatment. Laboratory data showed no specific underlying cause, such as vasculitis or collagen vascular disease, for the pulmonary hemorrhage. We therefore reached a diagnosis of a negative pressure pulmonary hemorrhage (NPPH) caused by upper airway obstruction. Follow-up examinations after 7 months showed no abnormal findings in the chest radiography or arterial blood gas analysis. To our knowledge, this is the first case of negative pressure pulmonary hemorrhage in japan.