American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Jul 2015
Tissue plasminogen activator potently stimulates pleural effusion via a monocyte chemotactic protein-1-dependent mechanism.
Pleural infection is common. Evacuation of infected pleural fluid is essential for successful treatment, but it is often difficult because of adhesions/loculations within the effusion and the viscosity of the fluid. Intrapleural delivery of tissue plasminogen activator (tPA) (to break the adhesions) and deoxyribonuclease (DNase) (to reduce fluid viscosity) has recently been shown to improve clinical outcomes in a large randomized study of pleural infection. ⋯ Mice treated with anti-MCP-1 antibody (P < 0.0001) or MCP-1 receptor antagonist (P = 0.0049) demonstrated a significant decrease in tPA-induced pleural fluid formation (by up to 85%). Our data implicate MCP-1 as the key molecule governing tPA-induced fluid accumulation. The role of MCP-1 in the development of other exudative effusions warrants examination.
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Am. J. Respir. Cell Mol. Biol. · Jul 2015
Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a destructive lung disease affecting women. LAM is caused by mutations in the tuberous sclerosis complex (TSC) genes. The TSC protein complex inhibits the mechanistic/mammalian target of rapamycin complex 1 (mTORC1), which is a master regulator of cellular metabolism. ⋯ Treatment with rapamycin or torin1 or down-regulation of sterol regulatory element-binding protein (SREBP), a lipogenic transcription factor, did not suppress LPC in TSC2-deficient cells. Inhibition of distinct isoforms of phospholipase A2 decreased the proliferation of TSC2-deficient cells. Collectively, these results demonstrate that TSC2-deficient cells have enhanced choline phospholipid metabolism and reveal a novel function of the TSC proteins in choline lysoglycerophospholipid metabolism, with implications for disease pathogenesis and targeted therapeutic strategies.
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Am. J. Respir. Cell Mol. Biol. · Jul 2015
Myeloid-specific Fos-related antigen-1 regulates cigarette smoke-induced lung inflammation, not emphysema, in mice.
Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. ⋯ Consistent with this result, bone marrow-derived Fra-1-null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD.
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Am. J. Respir. Cell Mol. Biol. · Jun 2015
Calcium restores the macrophage response to nontypeable haemophilus influenzae in chronic obstructive pulmonary disease.
Alveolar macrophages in chronic obstructive pulmonary disease (COPD) have demonstrated impaired bacterial phagocytosis and disordered cytokine secretion, which are calcium-dependent processes. We determined how calcium moderates the macrophage response to nontypeable Haemophilus influenzae (NTHI). We hypothesized that augmenting extracellular calcium during bacterial challenge would restore bacterial phagocytosis and cytokine secretion in monocyte-derived macrophages (MDMs) from subjects with COPD. ⋯ Specific calcium channel inhibitors abrogated calcium-mediated MARCO up-regulation and cytokine secretion. Extracellular calcium improved phagocytosis, restored innate cytokine secretion, and increased cell surface expression of bacterial recognition receptors, CD16 and MARCO. These observations support the therapeutic use of calcium to improve macrophage function in COPD to decrease exacerbations and chronic bacterial infection.
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Am. J. Respir. Cell Mol. Biol. · Jun 2015
Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs.
Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. ⋯ Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.