ABSTRACT
As activation of the coagulation system is both a consequence and contributor to acute lung injury (ALI), pulmonary coagulopathy has become a potential target for therapeutic intervention in ALI patients. We investigated the effects and possible mechanisms of endothelial cell (EC)-anchored tissue factor pathway inhibitor (TFPI) on lipopolysaccharide (LPS)-induced ALI in mice. To assess the effect of EC-anchored TFPI deletion on ALI indices, TFPI knockout (cKO) mice were generated. Mice were instilled by direct intratracheal injection LPS for the preparation of an ALI model. Evans blue dye (EBD) was injected intravenously 2âh prior to animal sacrifice (48âh post-LPS). Lungs were fixed for histopathology and the prepared tissue was homogenized or used to extract bronchoalveolar lavage fluid (BALF) or detect EBD concentration. TFPI knockdown mice with ALI were compared to wild-type (WT) mice with ALI to assess the effect of TFPI on endothelial barrier function and inflammation. TFPI deletion markedly exacerbated LPS histopathological changes in lung, and the LPS changes in protein, EBD extravasation, proinflammatory cytokines TNF-α, IL-1ß, and IL-6 in BALF in lung. The number and infiltration of white blood cells (WBCs) from BALF and lung tissue of TFPI cKO mice with LPS-challenged ALI was increased compared to WT mice with LPS-challenged ALI. We also found further increased toll-like receptor 4 and nuclear factor kappa-light-chain-enhancer of activated B cells activation and additional expression of vascular cell adhesion molecule 1 and reduction of angiotensin converting enzyme 2 expression in TFPI cKO+LPS mice compared with WT+LPS mice. Endothelial-specific TFPI deficiency promoted LPS-induced pulmonary inflammation and endothelial barrier permeability possibly via toll-like receptor 4-mediated nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway activation.
Subject(s)
Acute Lung Injury/immunology , Blood-Air Barrier/immunology , Endothelial Cells/immunology , Lipopolysaccharides/toxicity , Lipoproteins/immunology , NF-kappa B/immunology , Signal Transduction/immunology , Acute Lung Injury/chemically induced , Acute Lung Injury/genetics , Acute Lung Injury/pathology , Animals , Blood-Air Barrier/pathology , Cytokines/genetics , Cytokines/immunology , Endothelial Cells/pathology , Gene Knockout Techniques , Lipoproteins/genetics , Mice , Mice, Transgenic , NF-kappa B/genetics , Signal Transduction/geneticsABSTRACT
OBJECTIVE: To investigate resting energy expenditure (REE) and body composition and the relationship between substrate utilization and energy expenditure in urologic cancer patients. PATIENTS AND METHODS: Measured resting energy expenditure (mREE) was detected by indirect calorimetry in 122 urologic cancer patients and 131 control subjects. Extracellular fluid (ECF), intracellular fluid (ICF), and total water (TW) were measured by bioelectrical impedance appliance. Fat oxidation rate (F-O), carbohydrate oxidation rate, fat mass (FM), and fat free mass (FFM) were further determined. RESULTS: Compared with the controls, cancer patients showed significantly elevated mREE and mREE/FFM (P = 0.049; P < 0.001). Of all the cancer patients, 50% (n = 61) were hypermetabolic, 43.4% (n = 53) normometabolic, and 6.6% (n = 8) hypometabolic, whereas 35.1% (n = 46) of the controls were hypermetabolic, 56.5% (n = 74) normometabolic, and 8.4% (n = 11) hypometabolic. REE was correlated to substrate oxidation rate (R(2) = 0.710). Cancer patients exhibited no significant difference in FM, FM/body weight (BW) and FFM, compared with controls. Cancer patients presented no significant difference in TW compared with controls (P = 0.791), but they had increased ECF (P < 0.001) and decreased ICF (P < 0.001). CONCLUSION: Aberrations in substrate utilization may contribute to the elevated energy expenditure in urologic cancer patients. Cancer type and pathologic stage are influential factors of REE.
