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Biomedical subjects

M Humbert

Publications and source records attributed to M Humbert.

At least 109 records · Page 6Linked to original sources
PubMed2000

Severe pulmonary hypertension in histiocytosis X.

Diminished exercise capacity in advanced pulmonary histiocytosis X does not appear to be related to ventilatory limitation but may be related to pulmonary vascular dysfunction. Pulmonary hemodynamics and respiratory function were studied in 21 consecutive patients with advanced pulmonary histiocytosis X, and compared with parameters of patients with other severe chronic lung diseases (29 patients with chronic obstructive pulmonary disease and 14 patients with idiopathic pulmonary fibrosis). All patients with pulmonary histiocytosis X displayed severe pulmonary hypertension: mean pulmonary arterial pressure, 59 +/- 4 mm Hg; cardiac index, 2.6 +/- 0.8 L/min/m(2); and total vascular pulmonary resistance, 25 +/- 3 IU/m(2) (p < 0.05, as compared with patients with other chronic lung diseases). Pa(O(2)) was similar in the three groups, whereas FEV(1) was lower in patients with other chronic lung diseases (p < 0.05). In contrast to other chronic lung diseases, the degree of pulmonary hypertension was not related to variables of pulmonary function in pulmonary histiocytosis X. Histopathology was available for 12 patients with pulmonary histiocytosis X and revealed proliferative vasculopathy involving muscular arteries and veins, with prominent venular involvement. Two consecutive lung samples (taken before and after the occurrence of pulmonary hypertension) were available for six patients with pulmonary histiocytosis X, and showed that pulmonary vasculopathy worsened, whereas parenchymal and bronchiolar lesions remained relatively unchanged. These results indicate that pulmonary hypertension in pulmonary histiocytosis X might be related to an intrinsic pulmonary vascular disease, in which the pulmonary circulation is involved independent of small airway and lung parenchyma injury.

Adult↗
PubMed2000

Imbalance between platelet vascular endothelial growth factor and platelet-derived growth factor in pulmonary hypertension. Effect of prostacyclin therapy.

Focal vascular injury and impaired endothelial function are features of pulmonary hypertension (PH) that lead to enhanced platelet endothelial cell interactions. Vascular endothelial growth factor (VEGF) is contained in platelets and released at sites of vascular injury to promote endothelial repair and wound healing in combination with platelet-derived nonspecific mitogens such as platelet-derived growth factor (PDGF). The overall balance between platelet VEGF and PDGF was investigated in 21 patients with primary PH, 8 with secondary PH, and 27 with chronic hypoxemic lung disease (CHLD), as well as in 29 control subjects. Platelet VEGF content was increased in patients with primary and secondary PH as compared with control subjects (518 +/- 89, 675 +/- 156, and 166 +/- 29 fg/10(5) platelets, respectively; p < 0.01), whereas platelet PDGF content was similar in the three groups (31 +/- 2, 36 +/- 4, and 33 +/- 3 pg/10(5) platelets, respectively; NS). Patients treated with a continuous prostacyclin infusion had a higher platelet VEGF but a similar platelet PDGF content as compared with untreated patients. Moderate increases in platelet VEGF and PDGF contents were observed in the CHLD patients. We conclude that patients with primary or secondary PH have an increase in platelet VEGF content, but not in platelet PDGF content, and that their platelet VEGF content increases further in response to prostacyclin infusion. We suggest that imbalance between platelet VEGF and PDGF is beneficial to patients with PH.

Adolescent↗
PubMed2000

[Response to IgE].

Over the last three decades, a good deal of work has focused on the IgE response due to the implication of these antibodies in allergic diseases. IgE antibodies, mediators of immediate hypersensitivity reactions, bind to specific high or low affinity receptors which are distributed on cell surfaces throughout the organism. Activation of receptors contributes to the different aspects of allergic inflammation. Regulation of the IgE response is complex and involves different factors modulating isotype synthesis, low-affinity receptor FcERII:CD23 and its soluble portion, and the Th1/Th2 balance. Allergic diseases are characterized by a dysregulated IgE response, probably related to an imbalance favoring Th2 leading to exaggerated reaction. The advent of anti-IgE treatments can be seen as a notable progress in the management of atopic diseases. Their contribution will depend on the exact role of the IgE response in inflammatory allergic reactions.

Antigens↗
PubMed2000

[Does "intrinsic" asthma exist?].

Many asthmatics are not atopic. As compared to atopic ("extrinsic") asthma, nonatopic ("intrinsic") asthma occurs later in life, mostly in females, and nasal polyposis, aspirin sensitivity and corticodependence are common. In this patient population, there is no history of allergy, skin prick testing is negative for all aeroallergens tested and total as well as specific immunoglobulin E serum levels are within the normal range. Ten to forty percent of asthmatics are "intrinsic". It is important to define whether an asthmatic patient is atopic or not in order to recommend allergen avoidance in atopics. In the absence of allergy, it will be important to avoid bronchial irritants such tobacco, and in some patients aspirin and non steroidal anti-inflammatory agents. We will review recent findings obtained in a well defined population of atopic and nonatopic asthmatics. Analysis of bronchial mucosal expression of "pro-eosinophilic" and "pro-atopic" markers [IL-3, -4, -5, -13, GM-CSF, RANTES, MCP-3, IgE and high affinity IgE receptor (Fc epsilon RI)] demonstrates that there were more similarities than differences in immunopathology between atopic and nonatopic asthma.

Asthma↗
PubMed1999

Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics.

Atopic (AA) and nonatopic (NAA) asthma are characterized by chronic inflammation and local tissue eosinophilia. Many C-C chemokines are potent eosinophil chemoattractants and act predominantly via the CCR3. We examined the expression of eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), MCP-4, and CCR3 in the bronchial mucosa from atopic (AA) and nonatopic (intrinsic; NAA) asthmatics and compared our findings with atopic (AC) and nonatopic nonasthmatic controls (NC). Cryostat sections were processed for immunohistochemistry (IHC), in situ hybridization (ISH), and double IHC/ISH. Compared with AC and NC, the numbers of EG2+ cells and the cells expressing mRNA for eotaxin, eotaxin-2, RANTES, MCP-3, MCP-4, and CCR3 were significantly increased in AA and NAA (p < 0.01). Nonsignificant differences in these variants were observed between AA and NAA and between AC and NC. Significant correlations between the cells expressing eotaxin or CCR3 and EG2+ eosinophils in the bronchial tissue were also observed for both AA (p < 0.01) and NAA (p = 0.01). Moreover, in the total asthmatic group (AA + NAA) there was a significant inverse correlation between the expression of eotaxin and that of the histamine PC20 (p < 0.05). Sequential IHC/ISH showed that cytokeratin+ epithelial cells, CD31+ endothelial cells, and CD68+ macrophages were the major sources of eotaxin, eotaxin-2, RANTES, MCP-3, and MCP-4. There was no significantly different distribution of cells expressing mRNA for these chemokines between atopic and nonatopic asthma. These findings suggest that multiple C-C chemokines, acting at least in part via CCR3, contribute to bronchial eosinophilia in both atopic and nonatopic asthma.

Adolescent↗
PubMed1999

Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study.

Continuous intravenous epoprostenol improves exercise capacity, haemodynamics, and survival in severe primary pulmonary hypertension. Pulmonary hypertension can also be life-threatening in patients with connective tissue diseases. In a prospective open monocentre uncontrolled study, the effects of epoprostenol were evaluated in patients with severe pulmonary hypertension secondary to connective tissue diseases who were unresponsive to oral vasodilators (including calcium channel blockers) and continued to be in the New York Heart Association (NYHA) functional class III or IV despite conventional medical therapy. Seventeen patients received epoprostenol administered by a portable infusion pump associated with conventional therapy (oral anticoagulants, diuretics, supplemental oxygen). During the first six weeks of therapy, two (12%) patients died, of pulmonary oedema (n = 1) and severe sepsis (n = 1). In the fifteen remaining subjects, clinical and haemodynamic parameters improved significantly at six weeks. These patients were subsequently monitored for 80+/-48 (range 14-154) weeks after initiation of epoprostenol. Five (33%) patients died, of right heart failure (n = 2), severe sepsis (n = 2) or syncope (n = 1) and two patients were successfully transplanted 24 and 52 weeks after initiation of epoprostenol. Seven of the remaining eight patients had a persistent clinical improvement. Short-term epoprostenol therapy is effective in some patients with connective tissue diseases as demonstrated by better clinical status and haemodynamics at six weeks. However, this study reports several cases of early and late major complications including severe sepsis and pulmonary oedema. Additional information is needed to evaluate the benefit: risk ratio of long-term epoprostenol therapy in pulmonary hypertension secondary to connective tissue diseases.

Adult↗
PubMed1998

[Pulmonary thromboendarterectomy with video-angioscopy and circulatory arrest: an alternative to cardiopulmonary transplantation and post-embolism pulmonary artery hypertension].

The best predictor of poor or suboptimum outcome from pulmonary thromboendarterectomy (PTE) is insufficient relief of obstruction, especially in the lower lobes. The aim of this study is to emphasize that the use of video-assisted angioscopy may increase the quality of PTE and thus improve outcome. PTE included a median sternotomy, intrapericardial dissection limited to the superior vena cava, institution of cardiopulmonary bypass, deep hypothermia and sequential circulatory arrest periods. PTE was always bilateral and performed through two separate arteriotomies of both main intrapericardial pulmonary arteries. A rigid 5 mm angioscope connected to a video camera was introduced through the arteriotomy into the lumen to increase the visibility and perform the video-assisted endarterectomies of all obstructed segmental branches, including normally inaccessible anterior segmental branches. Between January 1996 and December 1997, 48 patients with severe postembolic pulmonary hypertension had PTE. Patients were in New York Heart Association (NYHA) class II (n = 2), III (n = 28) or IV (n = 18) with the following hemodynamics: mean pulmonary arterial pressure (PAP) 53 +/- 13 mmHg, cardiac index 2.16 +/- 0.5 L/min/m2, pulmonary vascular resistances (PVR): 1,152 +/- 414 dyne.s-1.cm-5. Six patients died from alveolar hemorrhage (n = 1), high residual pulmonary pressure and rethrombosis (n = 4) and hypoxic cardiac arrest (n = 1). The functional outcome in surviving patients was as follows: (NYHA) class I (n = 24), II (n = 16) or III (n = 2) with improved hemodynamics: mean pulmonary arterial pressure: 30 +/- 9 mmHg, cardiac index: 2.78 +/- 0.5 L/min/m2, pulmonary vascular resistances (PVR): 484 +/- 159 dynes.s-1.cm-5. Video-assisted angioscopy allows much improved quality and degree of pulmonary endarterectomy. This expands the indications to include patients with previously inaccessible distal disease and candidates for heart-lung transplantation.

Adult↗
PubMed1998

Expression of the IL-4 receptor alpha-subunit is increased in bronchial biopsy specimens from atopic and nonatopic asthmatic subjects.

BACKGROUND: Recent studies have provided evidence for increased IL-4 expression in the airways of atopic and nonatopic asthmatic subjects. IL-4 is believed to perform important regulatory roles in asthma; however, the expression of the IL-4 receptor has not been investigated. In this study we examined the mRNA and protein expression of the specific alpha-subunit of the IL-4 receptor (alphaIL-4R) in bronchial biopsy specimens obtained from atopic and nonatopic asthmatic subjects. METHODS: Asthmatic subjects and nonasthmatic control subjects were recruited, and lung function measurements were performed before bronchoscopy. Endobronchial biopsy specimens were examined for the presence of alphaIL-4R mRNA and immunoreactivity by using in situ hybridization and immunocytochemistry, respectively. RESULTS: alphaIL-4R mRNA-positive and immunoreactive cells were detected in the epithelium and subepithelium in biopsy specimens from all subjects. Expression of alphaIL-4R mRNA and protein was significantly increased in the epithelium and subepithelium of biopsy specimens from atopic asthmatic subjects compared with atopic control subjects (P <.05 and P <.001, respectively). Epithelial alphaIL-4R mRNA expression and immunoreactivity did not differ significantly between nonatopic asthmatic subjects and nonatopic control subjects. Although the numbers of alphaIL-4R mRNA-positive cells were augmented in the submucosa of intrinsic asthmatic subjects compared with nonatopic control subjects (P <.05), alphaIL-4R immunoreactivity did not differ significantly between these groups. Increased alphaIL-4R immunoreactive signals were also detected in the endothelial cell layer in both atopic and intrinsic asthmatic subjects compared with atopic and nonatopic control subjects, respectively (P <.05). Combined in situ hybridization immunocytochemistry performed on biopsy sections from asthmatic and control subjects demonstrated alphaIL-4R mRNA expression in CD3-positive T cells and tryptasepositive mast cells, with T cells comprising the larger proportion of alphaIL-4R mRNA-positive cells. Numbers of alphaIL-4R mRNA-positive or immunoreactive cells did not correlate with CD3-positive cell numbers, numbers of IL-4 mRNA-positive cells, or indices of pulmonary function. CONCLUSION: These results demonstrate constitutive alphaIL-4R expression in normal airways and enhanced expression in airway tissue from asthmatic individuals.

Adult↗
PubMed1998

Molecular concepts of IgE-initiated inflammation in atopic and nonatopic asthma.

Atopic and nonatopic (intrinsic) asthmatics were characterized by a broadly conserved bronchial mucosal proeosinophilic cytokine network in which IL-5 appears to play a key role. Inappropriate IgE-mediated mechanisms may occur in asthma, irrespective of its atopic status, as suggested by elevated serum IgE concentrations and bronchial mucosal expression of FcepsilonRI, IL-4, IL-13, Iepsilon, and Cepsilon. In general, these observations support the concept that these subtypes of asthma, despite showing distinct clinical and biologic features, share many common immunopathologic mechanisms. The most promising future directions of research regarding intrinsic asthma concern the possible identification of novel allergens or antigens, the detailed description of local bronchial mucosal IgE production, and the understanding of a possible macrophage dysfunction. Furthermore, a role for infectious (viral?) or autoimmune processes has yet to be firmly identified in intrinsic asthma. Animal models may also help us to understand the role of IgE and atopy in asthma. Although these are largely IgE-mediated mechanisms, allergen-induced bronchial hyperresponsiveness and eosinophilic inflammation can also occur in the absence of IgE (null mutation of the Cepsilon locus), as shown in a mouse model of hypersensitivity to Aspergillus fumigatus (57). Thus, despite the absence of atopy, IgE-mediated mechanisms may operate in intrinsic asthma (Fig. 1).

Animals↗
PubMed1998

Urinary cGMP concentrations in severe primary pulmonary hypertension.

BACKGROUND: Prognostic evaluation of patients with primary pulmonary hypertension (PPH) requires right heart catheterisation. The development of accurate non-invasive methods for monitoring these patients remains an important task. Cyclic guanosine monophosphate (cGMP) is an indicator of the action of natriuretic peptides and nitric oxide on target cells. Plasma and urinary cGMP concentrations are raised in patients with congestive heart failure in whom they correlate closely with haemodynamic parameters and disease severity. The aim of the present study was to determine whether the urinary concentration of cGMP could be used as a non-invasive marker of haemodynamic impairment in patients with severe PPH. METHODS: Urinary cGMP concentrations were measured in 19 consecutive patients with PPH, seven with acute asthma, and 30 normal healthy controls. RESULTS: Patients with PPH had higher urinary cGMP concentrations than asthmatic patients or normal healthy controls (p = 0.001). Urinary cGMP concentrations were higher in patients with severe haemodynamic impairment--that is, those with a cardiac index (CI) of < or = 2 l/min/m2 (p = 0.002)--and urinary cGMP concentrations were inversely correlated with CI (r = -0.69, p = 0.002) and venous oxygen saturation (r = -0.65, p = 0.003). CONCLUSION: Urinary cGMP concentrations may represent a non-invasive indicator of the haemodynamic status of patients with severe PPH.

Adult↗
PubMed1998

Increases in CD4+ T lymphocytes, macrophages, neutrophils and interleukin 8 positive cells in the airways of patients with bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic suppurative lung disease characterised by irreversible dilation of the bronchi and persistent purulent sputum. The immunopathology of the disease was studied using a quantitative immunostaining technique with particular reference to T lymphocytes, macrophages, and granulocytes. METHODS: Bronchial mucosal biopsy specimens were obtained by fibreoptic bronchoscopy from 12 patients with bronchiectasis (six receiving inhaled steroids) and 11 normal healthy controls. Immunostaining (APAAP method) was performed on frozen cryostat sections with a panel of monoclonal antibodies to total leucocytes (CD45), T lymphocyte phenotypic markers (CD3, CD4, CD8), macrophages (CD68), eosinophils (EG2), and neutrophils (elastase). RESULTS: There was a mononuclear cell infiltrate in both patients with bronchiectasis and normal controls, but an overall increase in total leucocyte cell numbers (CD45+ cells) was identified in those with bronchiectasis (median values 422 cells/mm2 versus 113 cells/mm2 in control tissue, p < 0.001). Intense infiltration of CD3+ T lymphocytes was observed compared with healthy controls (292 cells/mm2 and 40 cells/mm2, respectively, p < 0.001). This comprised predominantly CD4+ T cells (118 cells/mm2) rather than CD8+ T cells (47 cells/mm2). CD3+ cells counts were reduced in those subjects on inhaled steroids compared with those not receiving inhaled steroids (197 cells/mm2 versus 369 cells/mm2, p < 0.05), as were CD4+ cell counts (82 cells/mm2 versus 190 cells/mm2, p < 0.05). Neutrophil and macrophage cell numbers were also increased in patients with bronchiectasis (114 cells/mm2 and 213 cells/mm2, respectively) compared with controls (41 neutrophils/mm2 and 40 macrophages/mm2). EG2+ (activated) eosinophil numbers were much lower than T cells, macrophages, and neutrophils in patients with bronchiectasis but were increased compared with controls (36 cells/mm2 versus 0 cells/mm2, p < 0.001). In view of the markedly increased neutrophil counts in patients with bronchiectasis, biopsy specimens were immunostained for interleukin 8 (IL-8) which was highly significantly increased compared with controls (47 cells/mm2 versus 15 cells/mm2, p < 0.01). IL-8+ cells were less prominent in steroid treated patients than in patients not receiving treatment (30 cells/mm2 versus 60 cells/mm2, p < 0.05). A further characteristic of bronchiectasis was mucous gland hypertrophy. Gland area comprised up to 40% of the tissue in some bronchiectasis sections while no hypertrophy was noted in control biopsy specimens (p < 0.05). CONCLUSION: Airway inflammation in bronchiectasis is characterised by tissue neutrophilia, a mononuclear cell infiltrate composed mainly of CD4+ T cells and CD68+ macrophages, and increased IL-8 expression. Inhaled corticosteroid treatment in patients with bronchiectasis is associated with a less marked infiltration by T cells and IL-8+ cells within the bronchial mucosa, although this finding requires confirmation in a prospective placebo controlled trial.

Adult↗
PubMed1998

Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis.

Continuous intravenous epoprostenol (prostacyclin) produces hemodynamic and symptomatic responses and improves survival in patients with severe primary pulmonary hypertension refractory to conventional medical therapy. However, it has been recently shown that short-term infusion of epoprostenol can produce pulmonary edema in pulmonary veno-occlusive disease, presumably because of increased pulmonary perfusion in the presence of downstream vascular obstruction. We describe two additional cases of pulmonary edema complicating continuous intravenous epoprostenol in patients displaying severe pulmonary hypertension and pulmonary capillary hemangiomatosis, a rare condition characterized by the proliferation of thin-walled microvessels in the alveolar walls. This report indicates that epoprostenol therapy should not be used in patients with severe pulmonary hypertension secondary to pulmonary capillary hemangiomatosis.

Adult↗
PubMed1998

Increased expression of high affinity IgE (FcepsilonRI) receptor-alpha chain mRNA and protein-bearing eosinophils in human allergen-induced atopic asthma.

FcepsilonRI receptors play an important role in allergen-induced mediator release and antigen presentation by mast cells, basophils, and monocyte/macrophages in atopic disorders. The expression of FcepsilonRI by tissue eosinophils in atopic asthma after allergen challenge has not been established. For this reason we attempted to identify mRNA and protein product + FcepsilonRIalpha eosinophils in cytospins made from bronchoalveolar lavage (BAL) from atopic asthmatics (n = 9) and nonatopic normal subjects (n = 4) 24 h after segmental challenge with allergen or diluent. Messenger RNA for FcepsilonRIalpha was determined using in situ hybridization and FcepsilonRIalpha protein expression by immunocytochemistry using a mouse monoclonal antibody 22E7. Colocalization of FcepsilonRIalpha receptors to eosinophils was performed using chromotrope 2R. When compared with a control challenge, segmental challenge with Dermatophagoides pteronyssinus induced significant BAL eosinophilia (p = 0.007). The total number of BAL FcepsilonRIalpha mRNA and protein-positive cells also increased in asthmatics, median values 2 (0.7-7.2) and 11.5 (0.6-65.0) x 10(6) cells (p = 0.02) and 0 (0-0.3 x 10(6)) and 3.1 x 10(6) (0.45 - 162.5 x 10(6)) cells (p = 0.007), respectively, for mRNA and protein. Net increases in FcepsilonRIalpha+ cells correlated with the net increases in BAL eosinophils (r = 0.98, p = 0.0001 for mRNA and r = 0.72, p = 0.02 for protein). Colocalization studies with chromotrope 2R revealed that only 4% of FcepsilonRIalpha+ cells were eosinophils after control challenge and, in contrast, 85 to 95% of FcepsilonRIalpha+ cells were eosinophils after allergen. There were no differences in the numbers of FcepsilonRIalpha+ cells or eosinophils in normal control subjects. Our results demonstrated that local endobronchial allergen provocation in atopic asthmatics results in increased synthesis and expression of FcepsilonRIalpha predominantly on BAL eosinophils.

Adult↗
PubMed1998

Allergen-induced proliferation and interleukin-5 production by bronchoalveolar lavage and blood T cells after segmental allergen challenge.

In order to detect and characterize allergen-specific T cells in the airways of atopic asthmatics, we measured proliferation and cytokine production by bronchoalveolar lavage (BAL) T cells isolated from Dermatophagoides pteronyssinus (Der p)-sensitive asthmatics and nonatopic control subjects, and compared the results with those generated using peripheral blood (PB) T cells. BAL and PB mononuclear cells were collected 24 h after segmental allergen challenge by fibreoptic bronchoscopy and venepuncture, respectively. T cells purified from BAL and PB were stimulated with autologous, irradiated antigen-presenting cells and D. pteronyssinus extract or a control, nonallergen antigen (M. tuberculosis purified protein derivative [PPD]). IL-5 and IFN-gamma concentrations were measured in culture supernatants by ELISA, and T-cell proliferation by 3H-thymidine uptake. D. pteronyssinus-induced proliferation of T cells derived from both BAL and PB was elevated in asthmatics when compared with control subjects (p < 0.05), whereas PPD-induced proliferation was equivalent in both compartments. In the asthmatics, D. pteronyssinus-induced proliferative responses of equivalent numbers of BAL and PB T cells obtained after allergen challenge were statistically equivalent. Nevertheless, BAL T cells stimulated with D. pteronyssinus produced significantly greater amounts of IL-5 than did PB T cells (p < 0.05). Allergen-induced proliferation and IL-5 production by BAL T cells in the asthmatics after segmental allergen challenge correlated with the percentages of eosinophils in the BAL fluid (p < 0.01). Further, BAL T cells from asthmatic patients produced significantly higher amounts of IL-5 than did the same number of cells from nonatopic control subjects (p < 0.05). We conclude that, in D. pteronyssinus-sensitive asthmatics, allergen-specific T cells can be detected in the bronchial lumen after allergen challenge and that allergen-induced proliferation and IL-5 production by these cells correlates with local eosinophil influx. Although bronchial luminal T cells show an equivalent proliferative response to allergen stimulation as compared with PB T cells, they do produce more IL-5, consistent with the hypothesis that local differentiation or priming of these cells within the bronchial mucosal environment results in upregulation of allergen-induced IL-5 secretion.

Adult↗
PubMed1998

Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension.

Dexfenfluramine and fenfluramine greatly increase the risk of developing pulmonary hypertension (PHT). The mechanism of anorexigen-associated PHT (AA-PHT) and the reason PHT occurs in a minority of people exposed are unknown. Anorexigens are weak pulmonary vasoconstrictors, but they become potent when synthesis of the endogenous vasodilator nitric oxide (NO) is suppressed. We hypothesized NO deficiency predisposes affected individuals to develop AA-PHT. A prospective, case-control, study was performed on consecutive patients with AA-PHT (n = 9). Two sex-matched control groups were selected: patients with primary PHT (P-PHT, n = 8) and normal volunteers (n = 12). Lung NO production (VNO) and systemic plasma oxidation products of NO (NOx) were measured at rest and during exercise. AA-PHT developed 17 +/- 6 mo after a short course of anorexigen (6 +/- 2 mo) and was irreversible. VNO was lower in AA-PHT than in P-PHT and correlated inversely with PVR (p < 0.05). The apparent VNO deficiency may have resulted from increased oxidative inactivation of NO in patients with AA-PHT, as their NOx levels were elevated (p < 0.05) in inverse proportion to VNO (r2 = 0. 55; p < 0.02). In susceptible persons, anorexigens can cause an irreversible syndrome of PHT, hypoxemia, and systemic vascular complications after brief exposures. These patients have a relative NO deficiency years after discontinuing the anorexigen, perhaps explaining their original susceptibility.

Adult↗