Biomedical subjects
Publications and source records attributed to H J Carveth.
We describe the rare occurrence of a granulomatous pneumonitis seen in a patient following allogeneic bone marrow transplantation. Interestingly sarcoidosis was diagnosed in the marrow donor less than a year after donating his bone marrow.
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Neutrophil degranulation is an important event in inflammatory responses. We examined the regulation of neutrophil (PMN) degranulation by resting and activated human endothelial cells. Whereas PMNs adherent to endothelial cells that were stimulated to express P-selectin and platelet-activating factor did not release the specific granule marker lactoferrin or the primary granule enzyme, elastase, PMNs adherent to endothelial cells stimulated with interleukin-1 (IL-1) or tumor necrosis factor secreted both. PMN degranulation was dependent on the time of incubation of endothelial cells with the cytokine, its concentration, and the time of incubation of the PMNs with endothelial cells. Degranulation of PMNs and their adhesion to stimulated endothelial cells are correlated events, but they could be dissociated by blocking the tethering molecules used by the endothelial cells and neutrophils under these conditions. This suggested that paracrine signaling molecules that induce PMN degranulation are produced by cytokine-stimulated endothelial cells. We found that endothelial cells stimulated with IL-1 release newly synthesized degranulating factors that require transcription and translation. IL-8 was synthesized, released, and signaled granular secretion by PMNs. However, experiments with blocking antibodies indicated the presence of an additional degranulating factor not accounted for by IL-8. These experiments demonstrate that human endothelial cells regulate degranulation of neutrophils by generating signaling factors that are expressed differentially depending on the endothelial agonist and other features. Active modification of neutrophil granular secretion by endothelial cells can influence physiologic acute inflammatory responses but may also contribute to pathologic vascular and tissue damage.
A randomized, controlled clinical trial was performed with patients with acute respiratory distress syndrome (ARDS) to compare the effect of conventional therapy or inhaled nitric oxide (iNO) on oxygenation. Patients were randomized to either conventional therapy or conventional therapy plus iNO for 72 h. We tested the following hypotheses: (1) that iNO would improve oxygenation during the 72 h after randomization, as compared with conventional therapy; and (2) that iNO would increase the likelihood that patients would improve to the extent that the FI(O2) could be decreased by > or = 0.15 within 72 h after randomization. There were two major findings. First, That iNO as compared with conventional therapy increased Pa(O2)/FI(O2) at 1 h, 12 h, and possibly 24 h. Beyond 24 h, the two groups had an equivalent improvement in Pa(O2)/FI(O2). Second, that patients treated with iNO therapy were no more likely to improve so that they could be managed with a persistent decrease in FI(O2) > or = 0.15 during the 72 h following randomization (11 of 20 patients with iNO versus 9 of 20 patients with conventional therapy, p = 0.55). In patients with severe ARDS, our results indicate that iNO does not lead to a sustained improvement in oxygenation as compared with conventional therapy.
Much has been learned in the 35 years since the Dutch Hypothesis proposed early identification and intervention in those at risk for COPD. More has been accomplished in identification than in therapy. This is due in part to the powerful addiction of cigarette smoking and the continued search for effective pharmacologic means to prevent the accelerated loss in lung function. The Dutch Hypothesis states that airways hyperresponsiveness predicts future acceleration of the rate of lung function decline, particularly in susceptible smokers. In the Lung Health Study, heightened bronchoconstrictor response to methacholine did, indeed, strongly predict an adverse longitudinal decline in lung function. Further, airway hyperresponsiveness was more common than previously suspected, particularly in women. In this subgroup of cigarette smokers, selected because of early COPD, the incidence of hyperresponsiveness was 62% in men and 87% in women, rather than the anticipated 20%. In addition, in the Lung Health Study data recently released, female continuous smokers with the greatest degree of airway hyperresponsiveness exhibited the fastest rate of decline in lung function. However, cigarette smoking had a greater negative impact than hyperresponsiveness. Those with the greatest responsiveness who quit smoking declined more slowly than those with the least responsiveness who continued to smoke. The evidence continues to mount that smoking cessation should be the first and single most important intervention to prevent COPD. Many studies have demonstrated the beneficial effect of smoking cessation on declining lung function. In the comparison of the randomized groups, the Lung Health Study gives the strongest evidence to date that smoking cessation results in substantial benefit to lung function; the benefit continued to increase during the five year study. There was no evidence in the Lung Health Study that bronchodilator usage prevents the relentless decline in lung function in COPD. The increase of FEV1 among users of ipratroprium (even among the most-compliant) was not sustained when the bronchodilator was discontinued at the end of the study.
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Neutrophil activating factor is a polypeptide cytokine released from stimulated mononuclear phagocytes and endothelial cells. We found that neutrophil activating factor induced time- and concentration-dependent binding of human polymorphonuclear leukocytes to endothelial monolayers and subendothelial matrix proteins, via a mechanism that involves altered expression of the leukocyte CD11/CD18 glycoproteins. Thus, neutrophil activating factor is a third mediator, in addition to platelet-activating factor and endothelial leukocyte adhesion molecule 1, that is synthesized by activated endothelium and that can induce polymorphonuclear leukocyte adhesion to endothelial cells. Because NAF is released into the pericellular fluid, it may also stimulate binding of the leukocytes to exposed subendothelial structures at sites of vascular injury.
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