Shu-ichi Yamashita

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-β1 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.

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.

Hepatic portal venous gas in a patient undergoing chemotherapy for non-small cell lung cancer

A 71-year-old man was diagnosed with c-stage IV non-small cell lung cancer and treated with anticancer chemotherapy. On the 29th day of chemotherapy, the patient had slight upper abdominal fullness and pain. Ultrasonography showed gas flow in the portal vein and computed tomography confirmed the presence of gas in the peripheral lesion of the liver. We made a diagnosis of hepatic portal venous gas. He was successfully treated with conservative management. No mechanical or bacterial factors were identified, and the occurrence of HPVG in our case was considered to be related to his cancer-bearing condition and the chemotherapy agents. Although HPVG during chemotherapy is extremely rare, we should be aware of this complication in patients undergoing chemotherapy.