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Thomas R Martin

Publications and source records attributed to Thomas R Martin.

40 records · Page 3Linked to original sources
PubMed2002

The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness.

CCR3 is a chemokine receptor initially thought specific to eosinophils but subsequently identified on TH2 cell subsets, basophils, mast cells, neural tissue, and some epithelia. Because of the prominent role of these cells in allergic disease, including asthma, we generated mice deficient in CCR3 to determine its contribution in a model of allergic airway disease. Here we show that CCR3 is important for the basal trafficking of eosinophils to the intestinal mucosa but not the lung. In contrast, CCR3 disruption significantly curtails eosinophil recruitment to the lung after allergen challenge, with the majority of the eosinophils being arrested in the subendothelial space. Further, a role for CCR3 in mast cell homing has been identified; after sensitization and allergen challenge, we find increased numbers of intraepithelial mast cells in the trachea of knockout mice. Physiologically, we find that the net result of these complex cell fates after sensitization and allergen challenge is a paradoxical increase in airway responsiveness to cholinergic stimulation. These data underscore a more complex role for CCR3 in allergic disease than was anticipated.

Allergens↗
PubMed2002

Increased angiostatin levels in bronchoalveolar lavage fluids from ARDS patients and from human volunteers after lung instillation of endotoxin.

Acute respiratory distress syndrome (ARDS) is characterized by a disruption of the alveolar-capillary barrier, due to both an epithelial and an endothelial dysfunction. Whereas epithelial apoptosis seems to be mainly mediated by Fas ligand, the mediators of endothelial damage remain to be identified. Angiostatin, a powerful inhibitor of angiogenesis in vivo, also specifically induces apoptosis in endothelial cells. The concentration of various enzymes that cleave angiostatin from plasminogen was reported to be significantly increased in bronchalveolar lavage (BAL) fluids from patients with ARDS. Therefore, in this study, we investigated whether angiostatin was generated during the pulmonary inflammatory response of both healthy subjects challenged with endobronchial endotoxin and in patients with ARDS. We found significantly elevated angiostatin levels in BAL fluids from patients at risk for and with early ARDS (up to 0.022% and 0.018% of total protein, respectively), as well as in BAL fluids from volunteers treated with endotoxin (up to 1.17% of total protein), as compared to BAL fluids from control patients (< 0.005% of total protein). These data suggest that angiostatin may contribute to the endothelial damage observed in ARDS, probably via an increased permeability of the alveolar capillary barrier, allowing for an intra-alveolar processing of its precursor plasminogen.

Adult↗
PubMedDate not supplied

Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome.

CONTEXT: Recent clinical trials have demonstrated a decrease in multiple organ dysfunction syndrome (MODS) and mortality in patients with acute respiratory distress syndrome (ARDS) treated with a protective ventilatory strategy. OBJECTIVE: To examine the hypothesis that an injurious ventilatory strategy may lead to end-organ epithelial cell apoptosis and organ dysfunction. DESIGN AND SETTING: In vivo animals: 24 rabbits with acid-aspiration lung injury were ventilated with injurious or noninjurious ventilatory strategies. In vitro: rabbit epithelial cells were exposed to plasma from in vivo rabbit studies. In vivo human: plasma samples from patients included in a previous randomized controlled trial examining a lung protective strategy were analyzed (lung protection group, n = 9 and controls, n = 11). MAIN OUTCOME MEASURES: In vivo animals: biochemical markers of liver and renal dysfunction; apoptosis in end organs. In vitro: induction of apoptosis in LLC-RK1 renal tubular epithelial cells. In vivo human: correlation of plasma creatinine and soluble Fas ligand. RESULTS: The injurious ventilatory strategy led to increased rates of epithelial cell apoptosis in the kidney (mean [SE]: injurious, 10.9% [0.88%]; noninjurious, 1.86% [0.17%]; P<.001) and small intestine villi (injurious, 6.7% [0.66%]; noninjurious, 0.97% [0.14%]; P<.001), and led to the elevation of biochemical markers indicating renal dysfunction in vivo. Induction of apoptosis was increased in LLC-RK1 cells incubated with plasma from rabbits ventilated with injurious ventilatory strategy at 4 hours (P =.03) and 8 hours (P =.002). The Fas:Ig, a fusion protein that blocks soluble Fas ligand, attenuated induction of apoptosis in vitro. There was a significant correlation between changes in soluble Fas ligand and changes in creatinine in patients with ARDS (R = 0.64, P =.002). CONCLUSIONS: Mechanical ventilation can lead to epithelial cell apoptosis in the kidney and small intestine, accompanied by biochemical evidence of organ dysfunction. This may partially explain the high rate of MODS observed in patients with ARDS and the decrease in morbidity and mortality in patients treated with a lung protective strategy.

Animals↗