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Biomedical subjects

N W Morrell

Publications and source records attributed to N W Morrell.

At least 19 recordsLinked to original sources
PubMed2006

Effects of nebulised iloprost on pulmonary function and gas exchange in severe pulmonary hypertension.

Nebulised iloprost is established therapy of severe pulmonary hypertension; however, the effects on the bronchoalveolar compartment have not been investigated so far. We studied the short- and long-term effects of nebulised iloprost on pulmonary function tests and gas exchange in 63 patients with severe pulmonary hypertension (idiopathic n=17, chronic thromboembolism n=15, connective tissue disease n=12, congenital heart disease n=11, respiratory diseases n=8). Patients received iloprost in increasing dose up to 140 micro g iloprost/24h via an ultrasonic nebuliser. Short-term effects were assessed before and after every nebulisation: peak expiration flow decreased in mean by 1.9% (423+/-98 to 415+/-98) and percutaneous oxygen saturation increased in mean by 0.7% (90+/-6 to 91+/-5) post-nebulisation. There were no significant differences concerning underlying diagnosis or dose of nebulised iloprost. Within 3 months, 9 patients stopped treatment due to non-compliance with frequent nebulisations (n=3), or severe side effects (n=4); 2 patients with additional obstructive lung disease developed bronchoconstriction. Long-term effects were assessed by pulmonary function tests and gas exchange parameters at baseline and after 3 months treatment. There were no significant differences after 3 months therapy neither in FEV(1), FVC, TLC, residual volume nor in diffusions capacity, SO(2) at rest and during 6 min walking test, also in respect of the underlying diseases. However, there was a significant increase in 6 min walking distance (6 MWD) after 3 months (246+/-113 to 294+/-115 m, P<0.05). In conclusion, treatment with nebulised iloprost leads to functional improvement in severe pulmonary hypertension without systematic adverse short- and long-term effects on pulmonary function test or gas exchange. Patients with additional obstructive lung disease might develop bronchoconstriction. Severe side effects leading to discontinuation of treatment occurred in 9% of patients.

Adolescent↗
PubMed2005

Phosphodiesterase type 5 and high altitude pulmonary hypertension.

BACKGROUND: This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH). METHODS: 689 subjects (313 men) of mean (SD) age 44 (0.6) years living above 2500 m were screened for HAPH by medical examination and electrocardiography, and 188 (27%) met the criteria for right ventricular hypertrophy. 44 underwent cardiac catheterisation and 29 (66%) had a resting mean pulmonary artery pressure (PAP) above 25 mmHg. 22 patients with a raised mean PAP were randomised to receive sildenafil (25 or 100 mg) or matching placebo taken 8 hourly for 12 weeks. RESULTS: At 3 months, patients on sildenafil 25 mg 8 hourly (n = 9) had a significantly (p = 0.018) lower mean PAP (-6.9 mmHg) at the end of the dosing interval than those on placebo (n = 8) (95% CI -12.4 to -1.3). The treatment effect for sildenafil 100 mg 8 hourly (n = 5) compared with placebo was -6.4 mm Hg (95% CI -12.9 to 0.1). Both doses improved 6 minute walk distance, the lower dose by 45.4 m (95% CI 11.5 to 79.4; p = 0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; p = 0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles. CONCLUSIONS: PDE5 is an attractive drug target for the treatment of HAPH and a larger study of the long term effects of PDE5 inhibition in HAPH is warranted.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

Activin Receptors, Type I↗
PubMed2003

In vivo assessment of lung inflammatory cell activity in patients with COPD and asthma.

The involvement of inflammatory cells in the pathogenesis of chronic obstructive pulmonary disease (COPD) and asthma is well established. This study aimed to quantify differences in inflammatory cell function in situ in these patients as compared to normal subjects. Positron emission tomography was used to assess neutrophil activity (18F-fluorodeoxyglucose (18FDG)) and macrophage accumulation (11C-PK11195) in six patients with COPD, six chronic asthmatics and five age-matched normal control subjects. 18FDG uptake was greater in COPD than in normal subjects, with no increase in asthmatics. The mean slope of 18FDG uptake, corrected for volume of distribution, was 4.0 min(-1) in COPD patients compared with 1.5 min(-1) in control subjects and 1.7 min(-1) in asthmatics. Mean 11C-PK11195 uptake (plateau tissue:plasma) was higher in four of six COPD patients (10.8) and three of five asthmatics (11.8) than the maximum value in control subjects (6.2). From this preliminary study the authors conclude that positron emission tomography may be useful to assess polymorphonuclear neutrophil and macrophage activity in vivo in chronic obstructive pulmonary disease and asthma, and may reveal differences in cell behaviour between the study groups. In addition, positron emission tomography may provide indices of disease activity for future therapeutic studies.

Aged↗
PubMed2001

Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins.

BACKGROUND: Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-beta superfamily members. METHODS AND RESULTS: For studies of (3)H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour incubation with TGF-beta(1) (10 ng/mL) or bone morphogenetic protein (BMP)-2, -4, and -7 (100 ng/mL) inhibited basal and serum-stimulated (3)H-thymidine incorporation, and TGF-beta(1) and BMPs inhibited the proliferation of serum-stimulated PASMCs. In contrast, TGF-beta(1) stimulated (3)H-thymidine incorporation (200%; P<0.001) and cell proliferation in PASMCs from PPH but not from patients with secondary pulmonary hypertension. In addition, BMPs failed to suppress DNA synthesis and proliferation in PASMCs from PPH patients. Reverse transcription-polymerase chain reaction of PASMC mRNA detected transcripts for type I (TGF-betaRI, Alk-1, ActRI, and BMPRIB) and type II (TGF-betaRII, BMPR-II, ActRII, ActRIIB) receptors. Receptor binding and cross-linking studies with (125)I-TGF-beta(1) confirmed that the abnormal responses in PPH cells were not due to differences in TGF-beta receptor binding. Mutation analysis of PASMC DNA failed to detect mutations in TGF-betaRII and Alk-1 but confirmed the presence of a mutation in BMPR-II in 1 of 5 PPH isolates. CONCLUSIONS: We conclude that PASMCs from patients with PPH exhibit abnormal growth responses to TGF-beta(1) and BMPs and that altered integration of TGF-beta superfamily growth signals may contribute to the pathogenesis of PPH.

Activin Receptors↗
PubMed2001

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.

Activin Receptors↗
PubMed2001

Sildenafil inhibits hypoxia-induced pulmonary hypertension.

BACKGROUND: This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice. METHODS AND RESULTS: In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O(2) for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean+/-SD mm Hg]: normoxia 16.0+/-2.1 versus hypoxia 25.0+/-4.8) was almost abolished by sildenafil (normoxia 16.0+/-2.1 versus hypoxia 18.0+/-3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg. kg(-1). d(-1)) throughout 3 weeks of exposure to hypoxia (10% O(2)) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3+/-9.9 versus 29.9+/-9.7 mm Hg, P<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling. CONCLUSIONS: Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.

Adolescent↗
PubMed2001

Characterization of adenylyl cyclase isoforms in rat peripheral pulmonary arteries.

Activation of adenylyl cyclase (AC), of which there are 10 diversely regulated isoforms, is important in regulating pulmonary vascular tone and remodeling. Immunohistochemistry in rat lungs demonstrated that AC2, AC3, and AC5/6 predominated in vascular and bronchial smooth muscle. Isoforms 1, 4, 7, and 8 localized to the bronchial epithelium. Exposure of animals to hypoxia did not change the pattern of isoform expression. RT-PCR confirmed mRNA expression of AC2, AC3, AC5, and AC6 and demonstrated AC7 and AC8 transcripts in smooth muscle. Western blotting confirmed the presence of AC2, AC3, and AC5/6 proteins. Functional studies provided evidence of cAMP regulation by Ca(2+) and protein kinase C-activated but not G(i)-inhibited pathways, supporting a role for AC2 and a Ca(2+)-stimulated isoform, AC8. However, NKH-477, an AC5-selective activator, was more potent than forskolin in elevating cAMP and inhibiting serum-stimulated [(3)H]thymidine incorporation, supporting the presence of AC5. These studies demonstrate differential expression of AC isoforms in rat lungs and provide evidence that AC2, AC5, and AC8 are functionally important in cAMP regulation and growth pathways in pulmonary artery myocytes.

Adenylyl Cyclases↗
PubMed2001

Adrenomedullin expression and growth inhibitory effects in distinct pulmonary artery smooth muscle cell subpopulations.

The vasodilator peptide adrenomedullin is elevated in patients with pulmonary hypertension and has been implicated in the inhibition of vascular remodeling. We questioned whether adrenomedullin is released by human pulmonary artery smooth muscle cells (PASMCs) and inhibits PASMC growth and release of endothelin, a known smooth muscle cell mitogen. The majority of PASMCs isolated from proximal pulmonary arteries and all PASMCs from distal pulmonary arteries released adrenomedullin, although at differing rates (mean, 177 +/- 28 and 62 +/- 11 fmol/10(5) cells/24 h, respectively). These cells were designated ADM+. However, some proximal PASMC isolates did not release adrenomedullin, designated ADM-. Northern blot analysis confirmed adrenomedullin expression in proximal ADM+ but not ADM- isolates. ADM- and distal ADM+ PASMCs proliferated faster in serum than did proximal ADM+ cells. Adrenomedullin potently and dose-dependently (mean EC(50) = 2.2 +/- 0.5 nM) increased intracellular cyclic adenosine monophosphate (cAMP) in ADM- isolates via specific adrenomedullin receptors. In contrast, both adrenomedullin and calcitonin gene-related peptide modestly elevated cAMP in 50% of ADM+ isolates. Adrenomedullin dose-dependently inhibited platelet-derived growth factor-stimulated [3H]thymidine incorporation and endothelin release in ADM- cells but did not affect [3H]thymidine uptake in ADM+ isolates. We conclude that distinct subpopulations of human PASMCs release and respond to adrenomedullin. The heterogeneity of adrenomedullin release and the inhibition of PASMC DNA synthesis and endothelin release suggest that adrenomedullin may function as a paracrine mediator in the inhibition of pulmonary vascular remodeling.

Adrenomedullin↗