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K R Stenmark

Publications and source records attributed to K R Stenmark.

87 records · Page 5Linked to original sources
PubMed1987

Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m.

Some human newborns have a syndrome characterized by irreversible pulmonary hypertension and severe hypoxemia and by medial hypertrophy and adventitial thickening of pulmonary arteries. We considered that newborn calves made severely hypoxic might reproduce features of the human disease. When 2-day-old calves were placed at 4,300 m simulated altitude, pulmonary arterial pressure was increased and could be reversed by 100% O2. However, after 2 wk at 4,300 m, pulmonary arterial pressures were suprasystemic and there was right-to-left shunting probably through the foramen ovale and a patent but restrictive ductus arteriosus. Suprasystemic pulmonary pressure and hypoxemia persisted with 100% O2 breathing. Morphometrical examination of the lung arteries showed a markedly thickened adventitia with cellular proliferation and collagen and elastin deposition. There was increased medial thickness and distal muscularization of the pulmonary arteries associated with decreased luminal diameter. The rapid development of severe pulmonary hypertension and poor responsiveness to O2 was associated with increased arterial wall thickness, particularly involving the adventitia. Thus the pulmonary arterial circulation in these calves, which were placed at high altitude for 2 wk, exhibited features resembling persistent pulmonary hypertension in newborn infants.

Altitude Sickness↗
PubMed1986

[Inhibition of hypoxic pulmonary vasoconstriction by leukotriene blockade].

The mechanism of hypoxic pulmonary vasoconstriction is still unclear. Since leukotrienes are pulmonary vasoconstrictors and lung cells are able to produce leukotrienes, it has been proposed that leukotrienes are mediators of hypoxic pulmonary vasoconstriction and then inhibition of their synthesis should block hypoxic pressure responses. In order to test this hypothesis we investigated whether diethylcarbamazine (DEC), a known leukotriene synthesis blocker, blocks hypoxic pulmonary vasoconstriction in isolated rat lungs. DEC blocked ongoing and subsequent hypoxic pressure responses in a relatively specific and dose-dependent fashion. We therefore extended our observations to awake rats and found that DEC reversibly inhibited acute hypoxic pulmonary vasoconstriction. Furthermore, pulmonary hypertension and right ventricular hypertrophy in rats exposed to chronic hypobaric hypoxia could be prevented by DEC treatment. From these data we conclude that DEC inhibits both acute and chronic hypoxic pulmonary vasoconstriction. Thus, leukotrienes could be important mediators of hypoxic pulmonary vasoconstriction.

Angiotensin II↗
PubMed1986

Analysis of leukotriene B4 in human lung lavage by HPLC and mass spectrometry.

Although leukotrienes are believed to mediate symptoms of human lung disease, there is little direct evidence of their existence in the lung. This is due to the difficulty in obtaining lung samples, the small amounts of leukotrienes typically present in such samples and the problems associated with purifying and analyzing leukotrienes in complex biological samples. In this study, lung lavagates were collected and analyzed for leukotrienes. The methods in this analysis included solid phase extraction using a C-18 reverse phase cartridge followed by HPLC using a new photodiode array detector which provides full UV spectra of eluting compounds. Lung lavage fluid from a patient with chronic pulmonary disease contained a compound with a UV spectra of LTB4 which was found to elute with synthetic [3H]-LTB4. This compound was confirmed as LTB4 using gas chromatography/mass spectrometry in the negative ion-chemical ionization mode. The inclusion of oxygen-18 LTB4 as an internal standard allowed approximate quantitation of the amount of LTB4 present in this 5 ml lung lavagate as 40-50 ng.

Chromatography, High Pressure Liquid↗
PubMed1985

Alveolar inflammation and arachidonate metabolism in monocrotaline-induced pulmonary hypertension.

We tested the hypothesis that monocrotaline would activate arachidonic acid metabolism in rats. If activation occurred before the pulmonary hypertension developed, arachidonate metabolites could play a role in the hypertensive monocrotaline injury. We found that 1 wk after monocrotaline administration 6-ketoprostaglandin F1 alpha and leukotriene C4 were increased in lung lavages. At 3 wk when pulmonary hypertension was well developed, lung lavage contained increased 6-ketoprostaglandin F1 alpha and thromboxane B2. In addition, the number and activity of white blood cells in the lavages was increased, and abnormal alveolar macrophages were present. The lung extract contained slow-reacting substances including leukotriene D4. Indomethacin administration inhibited the formation of cyclooxygenase metabolites but did not prevent pulmonary hypertension. Diethylcarbamazine administration reduced the numbers and activity of inflammatory cells, increased pulmonary hypertension, prevented right ventricular hypertrophy, and inhibited the formation of slow-reacting substances. We concluded that arachidonate metabolism was activated before pulmonary hypertension developed, that the inflammatory cells in the alveolus accompanied the hypertensive process, and that diethylcarbamazine attenuated both the monocrotaline-induced inflammatory response and the pulmonary hypertension.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Diethylcarbamazine inhibits acute and chronic hypoxic pulmonary hypertension in awake rats.

Leukotriene inhibitors preferentially inhibit the acute pressor response to hypoxia in isolated rat lungs. If leukotrienes are important in hypoxic pulmonary vasoconstriction, then inhibition of their synthesis could prevent the development of chronic hypoxic pulmonary hypertension. We found that diethylcarbamazine (DEC), a leukotriene synthesis blocker, reversibly inhibited acute hypoxic pulmonary vasoconstriction in the awake rat. Rats exposed to chronic hypobaric hypoxia showed pulmonary hypertension and the production of a slow-reacting substance compared with low altitude control rats. The higher of 2 doses of DEC blocked the pulmonary hypertension and the production of slow-reacting substance in all of the hypoxic rats treated. The lower dose of DEC attenuated the pulmonary hypertension in only some of the rats. Changes in weight gain, hematocrit, or generation of prostacyclin did not explain the prevention of the pulmonary hypertension by DEC. We conclude that diethylcarbamazine inhibits acute and chronic pulmonary hypertension in the intact rat.

Acute Disease↗
PubMed1984

Leukotriene C4 production during hypoxic pulmonary vasoconstriction in isolated rat lungs.

Leukotriene inhibitors preferentially inhibit hypoxic pulmonary vasoconstriction in isolated rat lungs. If lipoxygenase products are involved in the hypoxic pressor response they might be produced during acute alveolar hypoxia and a leukotriene inhibitor should block both the vasoconstriction and leukotriene production that occurs in response to hypoxia. We investigated in isolated blood perfused rat lungs whether leukotriene C4 (LTC4) could be recovered from whole lung lavage fluid during ongoing hypoxic vasoconstriction. Lung lavage from individual rats had slow reacting substance (SRS)-like myotropic activity by guinea pig ileum bioassay. Pooled lavage (10 lungs) as analyzed by reverse phase high performance liquid chromatography had an ultraviolet absorbing component at the retention time for LTC4. At radioimmunoassay, and SRS myotropic activity by bioassay. LTC4 was not found during normoxic ventilation, during normoxic ventilation after a hypoxic pressor response, or during vasoconstriction elicited by KCl. Diethylcarbamazine citrate, a leukotriene synthesis blocker, concomitantly inhibited the hypoxic vasoconstriction and LTC4 production. Thus 5-lipoxygenase products may play a role in the sequence of events leading to hypoxic pulmonary vasoconstriction.

Animals↗
PubMed1984

Actions of lipoxygenase metabolites in isolated rat lungs.

Leukotrienes constrict smooth muscle and could be important for the regulation of the pulmonary circulation. We examined the production and action of lipoxygenase metabolites in isolated lungs, where we controlled the perfusing fluid used. Arachidonate injected into isolated rat lungs perfused with cell- and protein-free physiological salt solution caused a transient pressor response. Following indomethacin, arachidonate caused a delayed slow pressure rise followed by edema. The lung effluent contracted the guinea pig ileum. High-pressure liquid chromatography (HPLC) analysis of the perfusate demonstrated the presence of leukotrienes (LTC4 and LTD4). Diethylcarbamazine, a leukotriene synthesis inhibitor, prevented the slow pressure rise and edema seen after indomethacin plus arachidonate. In lungs perfused with cell- and protein-free physiological salt solution, LTC4, but not LTD4, caused a transient pressure rise followed by a sustained pressure rise. The sustained rise was abolished by a leukotriene-receptor blocker (FPL 55712) but not by indomethacin. In blood-perfused lungs, LTC4 caused only the transient pressure rise that was not blocked by FPL 55712. In lungs perfused with physiological salt solution containing albumin, LTC4 had no effect. We concluded that 1) perfused nonsensitized rat lungs produced LTC4 and LTD4; 2) LTC4 may be a major pulmonary vasoconstrictor; and 3) albumin binding limits the pressor effect of LTC4.

Animals↗
PubMed1983

Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension.

Persistent pulmonary hypertension of the newborn is a syndrome consisting of severe hypoxemia and pulmonary hypertension that appears within hours of birth. Since certain leukotrienes (C4, D4, and E4) are known to produce some of the features of persistent pulmonary hypertension of the newborn, including pulmonary vasoconstriction, bronchoconstriction, decreased lung compliance, and pulmonary edema, we studied five newborns with the syndrome to determine whether these leukotrienes were present in their airways. We found leukotriene C4 and leukotriene D4 in the lung lavage fluids of all five newborns who had the clinical diagnosis of persistent pulmonary hypertension and who required ventilatory assistance. In contrast, leukotrienes were not demonstrated in a control group of 14 infants requiring ventilatory assistance who did not have the clinical diagnosis of persistent pulmonary hypertension. We conclude that leukotrienes may have a role in persistent pulmonary hypertension of the newborn.

Animals↗
PubMed1983

Abnormal alveolar cells in monocrotaline induced pulmonary hypertension.

Monocrotaline given to rats causes lung injury which is followed by pulmonary hypertension. A large, abnormal intraalveolar cell has been repeatedly observed. The purpose of the present study was to define the nature of the cell and to determine how it related to the lung injury. As observed by electron microscopy, the intraalveolar cell contained numerous large, dense granules, as well as lipid whorls, extensive Golgi complexes, and many small vesicles. These cells appeared to be macrophages, possibly altered by ingestion of lipid-like material which was free in the alveolar space. Enlarged type II pneumonocytes and mast cells were seen in the alveolar walls but their appearance differed from that of the free alveolar cells. The electron microscopic findings plus the presence of Fc and C3b receptors on the cells indicated they were alveolar macrophages. When the severity of pulmonary hypertension was varied by a) giving monocrotaline to rats of varying age, b) by varying the dose of monocrotaline, or c) by varying the time interval after monocrotaline administration, the number of abnormal alveolar macrophages related to the severity of the pulmonary hypertension. When we reduced the number of circulating leukocytes by whole body radiation, monocrotaline administration was followed both by accelerated pulmonary hypertension and increased numbers of abnormal alveolar macrophages. The abnormal macrophage appeared to be a marker of the monocrotaline induced pulmonary hypertension. However, neither the abnormal macrophage nor the monocrotaline injury appeared to depend on circulating leukocytes.

Animals↗
PubMedDate not supplied

Connective tissue growth factor expression in pediatric myofibroblastic tumors.

Human connective tissue growth factor (CTGF) is a secreted cysteine-rich peptide and a member of the peptide family that includes serum-induced immediate gene products such as a v-src-induced peptide and a putative proto-oncogene, c-src. CTGF is secreted by endothelial cells, fibroblasts, smooth muscle cells, and myofibroblasts. Its expression is increased in various human and animal fibrotic diseases. We hypothesized that tumors with significant fibrous and vascular components would exhibit increased expression of CTGF. We examined the expression of CTGF mRNA by in situ hybridization in 12 pediatric tumors and tumor-like conditions, including angiofibroma, malignant fibrous histiocytoma, infantile myofibromatosis, and malignant hemangiopericytoma. All the tumors showed moderate to intense CTGF expression in tumor cells and/or endothelial cells of the associated vasculature. Angiofibromas expressed CTGF only in factor VIII-positive endothelial cells and vascular smooth muscle cells. In contrast, infantile myofibromatosis, malignant hemangiopericytomas, and fibrous histiocytomas expressed CTGF in both endothelial cells and in vimentin-positive tumor cells, particularly those around the blood vessels. CTGF mRNA was not detected in the inflammatory cells observed in many of the tumors. The presence of CTGF in the endothelial cells and tumor cells around blood vessels raises the possibility that CTGF is involved in the pathogenesis of these myofibroblastic tumors.

Adolescent↗
PubMedDate not supplied

Respiratory syncytial virus infects the Bonnet monkey, Macaca radiata.

The Bonnet monkey model of respiratory syncytial virus (RSV) infection may be a useful nonhuman primate model for studying RSV disease in humans because Bonnet monkeys can predictably be infected to obtain an orderly sequence of morphologic, cytologic, virologic, serologic, and inflammatory changes related to time of infection. Young feral Bonnet monkeys, Macaca radiata, were infected endotracheally with 10(6) plaque-forming units (pfu) of the Long strain of RSV. RSV was recovered from the animals' lungs at necropsy on days 3, 5, and 7 with the highest viral titer obtained on day 3 (1.1 and 5.2 x 10(3) pfu/g of tissue in the upper and lower lobes, respectively). RSV antigen and F protein mRNA were detected 3-5 days after infection in alveolar macrophages and in the epithelium of bronchi, terminal bronchioles, and alveoli. Histologic analysis of RSV-infected lungs at necropsy revealed progressive bronchiolar mucosal and submucosal inflammation, periarterial mononuclear interstitial inflammation, and focal alveolitis, with a maximal response at 7 days after infection. Cell counts in bronchoalveolar lavage (BAL) increased with time with neutrophils and macrophages predominating on day 3 (6.47 and 5.85 x 10(5)/mm3, respectively) and lymphocytes predominating on day 9 (4.18 x 10(5)/mm3). Serum-neutralizing antibody appeared on day 5 and IgG antibody to RSV was detected on day 9. This sequence of morphologic, cytologic, virologic, serologic, and inflammatory change following RSV infection creates a useful model in the study of experimentally induced RSV disease with a potential for testing future vaccine-induced alterations in RSV disease response.

Animals↗