Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients.

Primary pulmonary hypertension (PPH) is characterized by intimal fibrosis and cell proliferation (including fibroblasts, smooth muscle and endothelial cells) in the distal pulmonary arterial tree. Considerable interest has been generated by recent reports of PPH in human immunodeficiency virus (HIV)-1-infected individuals. Although the lack of evidence for a pulmonary artery infection has suggested that in such cases HIV may act through mediator release rather than by direct endothelial infection, the mechanisms underlying HIV-associated PPH remain poorly defined. Platelet-derived growth factor (PDGF) has the ability to induce smooth muscle cell and fibroblast proliferation and migration. Given these considerations, we have attempted to document a possible role for PDGF in PPH occurring in HIV seropositive and seronegative patients. Using semiquantitative polymerase chain reaction (PCR), PDGF A-chain messenger ribonucleic acid (mRNA) expression was analysed in surgical lung biopsies from 13 HIV seronegative patients and one HIV seropositive patient, all displaying severe PPH. In parallel, lung samples from two patients with HIV-1-associated PPH were studied by immunohistochemistry and in situ hybridization. Results were compared to those obtained in three HIV-1-infected individuals with no pulmonary complication (as demonstrated by clinical, radiological, bacteriological, and necropsy findings) and five control lung biopsies. As compared to controls, PDGF A-chain mRNA expression is elevated in lung biopsies from patients displaying PPH (p=0.029). In HIV-1-associated PPH, interstitial perivascular cells expressing PDGF A-chain mRNA and protein could be detected by in situ hybridization and immunohistochemistry, respectively. Platelet-derived growth factor expression is elevated in lung biopsies of patients displaying primary pulmonary hypertension. Growth factors such as platelet-derived growth factor may play a part in the initiation and/or progression of primary pulmonary hypertension.

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.

Intrapulmonary production of RANTES during rejection and CMV pneumonitis after lung transplantation.

RANTES (regulated upon activation, normally T expressed and secreted) is a chemoattractant for macrophages, memory T lymphocytes, and eosinophils. We investigated whether intrapulmonary production of the chemokine RANTES contributes to the recruitment of immune cells during lung transplantation complications. RANTES concentration was measured in bronchoalveolar lavage (BAL) fluids using an ELISA assay. It was significantly higher during CMV pneumonitis (36.2 +/- l6 pg/ml, n=12, P=0.031) and allograft rejection (31.1 +/- 8.5 pg/ml, n=27, P=0.013) than in patients without complications (9.1 +/- 2.3 pg/ml, n=22). At least some of the RANTES was produced by lung macrophages: BAL macrophages cultured for 24 hr spontaneously released larger amount of RANTES during CMV pneumonitis (140 +/- 53 pg/ml, n=8, P=0.002) and allograft rejection (84 +/- 44 pg/ml, n=11, P=0.037) than in control patients (15.2 +/- 6.5 pg/ml, n=21). Moreover, macrophages in transbronchial biopsies were labeled by an anti-RANTES mAb. RANTES production by BAL macrophages was followed in 2 patients with CMV pneumonitis. It remained high as long as CMV-induced cytopathic effects or clinical symptoms were present, but it returned to baseline as the infection was controlled. These results suggest that the intrapulmonary production of the chemokine RANTES by activated macrophages contributes to the intrapulmonary accumulation of immune cells during complications of lung transplantation.

[Acute lipid pneumopathy]. / Pneumopathie aiguë lipidique.

BACKGROUND: Lipid pneumonia in children has rarely been described in Europe. In some countries, due to local customs, the course is chronic. This study describes an acute lipid pneumonia in a young boy. CASE REPORT: A 12 year-old boy, previously treated for a rhabdomyosarcoma, developed acute fever with thoracic pain. A chest radiograph revealed heterogenous consolidation. The patient was given oral antibiotics, although no improvement was observed. The diagnosis of lipid pneumonia was made by a bronchoscopy with bronchoalveolar lavage. Treatment with corticosteroids was started. Clinical manifestations improved rapidly. One month later, chest radiograph and biological findings were normal. CONCLUSION: Diagnosis of lipid pneumonia should be considered in children with an acute febrile pneumonitis non resolving with antibiotic treatment. Examination of the fluid obtained by bronchoalveolar lavage confirms the diagnosis.

Transforming growth factor beta in normal human lung: preferential location in bronchial epithelial cells.

BACKGROUND: Transforming growth factor beta (TGF-beta) is an immunomodulatory cytokine regulating the proliferation and differentiation of various cell types. It also contributes to the maintenance of tissue architecture by influencing the production of extracellular matrix components. TGF-beta has been detected in bronchoalveolar lavage fluid from normal human lung, but the nature and distribution of cells containing TGF-beta in this organ remain unknown. METHODS: Fourteen normal human lung specimens were studied by immunohistochemistry with a monoclonal antibody recognizing TGF-beta 1, TGF-beta 2 and TGF-beta 3. RESULTS: TGF-beta was detected in all cases. Bronchial epithelial cells contained the largest amounts of TGF-beta. In these cells the staining was brightest at the apical pole. Macrophages and smooth muscle cells also contained TGF-beta, although less than epithelial cells. No TGF-beta was detected in other cell populations, including endothelial cells, fibroblasts, and pneumocytes. CONCLUSIONS: The bronchial epithelial compartment appears to be the main location of TGF-beta in the normal human lung, suggesting that this cytokine has a pivotal role in the immunological properties of the bronchial mucosa.

[Pulmonary arterial hypertension of chronic thrombo-embolic origin. 70 patients]. / Hypertension artérielle pulmonaire d'origine thrombo-embolique chronique. 70 malades.

OBJECTIVES: Chronic thrombo-embolic pulmonary hypertension is a rare and aberrant outcome of acute pulmonary embolism. Because it has become a potentially curable form of pulmonary hypertension, the frequency of recognized cases has increased. We report a case series of 70 patients with chronic thromboembolic pulmonary hypertension evaluated in our institution between 1984 and 1993, and discuss diagnostic clues and therapeutic approaches. RESULTS: All patients complained of dyspnoea on exertion. A history of acute thrombo-embolic events and lung murmurs were found in 60% and 17% of patients respectively. Coagulation disorders were found in 30% of the patients tested; the most common abnormality was lupus anticoagulant. The key non-invasive study for diagnosis was the lung perfusion scan which showed at least one segmental or wider perfusion defects in all patients. Pulmonary angiography confirmed the diagnosis in all cases and, sometimes associated with intravascular ultrasound imaging, established the feasibility of thromboendarterectomy. Medical therapy included the use of long-term oral anticoagulant, and in case of lower limb venous thrombosis, inferior vena cava filtration. Finally two surgical procedures were discussed in selected patients: thromboendarterectomy and lung transplantation. Since 1988, eight patients have benefited from lung transplantation (six patients are still alive) and 11 patients underwent thromboendarterectomy which was successful in 9 patients leading to dramatic functional and haemodynamic improvement. CONCLUSION: Chronic thrombo-embolic pulmonary hypertension is a severe, sometimes fatal, disease which can be successfully treated by pulmonary thromboendartectomy and lung transplantation.

Pulmonary hypertension in patients with human immunodeficiency virus infection. Comparison with primary pulmonary hypertension.

BACKGROUND: Previously reported cases of patients with pulmonary hypertension (PH) and human immunodeficiency virus (HIV) infection are poorly documented regarding baseline hemodynamics and potential for pulmonary vasodilatation. The purpose of this report was to compare HIV-infected patients who had PH with non-HIV-infected patients who had primary pulmonary hypertension (PPH) in terms of (1) clinical characteristics, (2) hemodynamics in baseline conditions and during a short-term vasodilator trial with epoprostenol, and (3) survival. METHODS AND RESULTS: Between April 1987 and August 1992, 20 HIV-infected patients with PH and 93 non-HIV-infected patients with PPH were referred to our department. At the time of referral, baseline right-side heart hemodynamics were obtained in addition to demographic variables and medical history. A short-term vasodilator trial with epoprostenol was performed in 19 of 20 HIV-infected and 86 of 93 non-HIV-infected patients. Outcome and survival were analyzed and compared for both groups (22 transplant recipients were excluded from the group of patients with PPH). At the time of diagnosis of PH, HIV-infected patients significantly differed from non-HIV-infected patients in age (32 +/- 5 versus 42 +/- 13 years; P < .05) and degree of disability (New York Heart Association functional class III or IV, 50% versus 75%; P < .01). The proportion of disease states known to be associated with PPH (Raynaud's phenomenon, migraine, collagen disease without overt symptoms and signs, or a positive family history of PPH) was similar in the two groups. HIV-infected patients had a severe but significantly lower level of PH than patients with PPH. The percentage of responders to epoprostenol and the level achieved in pulmonary vasodilatation were similar in the two groups. PH was the cause of death in 8 of the 10 HIV-infected patients who died within 1 year after the diagnosis of PH. Overall survival was poor and not significantly different between the two groups. Pathological findings in lung tissue obtained from 3 HIV-infected patients were close to those seen in most of the lung specimens available from 27 patients with PPH and resembled plexogenic pulmonary arteriopathy. CONCLUSIONS: These results support the view that HIV infection may now be regarded as another common disease state that can be associated with PPH development. The lower initial severity in HIV-infected patients may be due to the close medical attention usually devoted to such patients, who may account for an earlier diagnosis. However, the overall survival rate of HIV-infected patients with PH appeared to be as poor as in non-HIV-infected patients with PPH.

Emergence of inflammatory alveolar macrophages during rejection or infection after lung transplantation.

Local activation of macrophages may play an important role in immune complications following lung transplantation. To document such a phenomenon, we have investigated the possible changes of alveolar macrophage surface antigen expression after lung transplantation. Using immunocytofluorometry, we have analyzed the phenotype of alveolar macrophages from 41 bronchoalveolar lavage fluids obtained from 19 lung transplant recipients displaying various complications. The strong expression of HLA-DR observed on almost all alveolar macrophages was similar among groups I (no complication), II (minimal acute rejection), and III (mild to severe acute rejection), but was enhanced in group IV (bronchial infection) (P < 0.03). We observed no significant variation in the monocyte lineage CD14 antigen expression among the 4 groups, and about 83% of alveolar macrophages expressed this marker strongly. Membrane expression of the 27E10 antigen that characterizes infiltrating macrophages in acute inflammatory lesions was significantly higher during mild to severe rejection episodes than in controls (P < 0.02) and during bronchial infections (P < 0.05) but not during minimal rejection. Double staining experiments confirmed that 27E10-positive cells in groups III and IV belonged to the macrophage lineage. In addition, the expression of the 27E10 antigen on cultured alveolar macrophages was found to be increased after stimulation by bacterial lipopolysaccharide or IFN-gamma. These results indicate that a particular alveolar macrophage subpopulation is activated during immune events after lung transplantation. This population, recognized by the 27E10 mAb, might be involved in cytokine production during severe acute rejection and infection episodes.

In situ production of interleukin-6 within human lung allografts displaying rejection or cytomegalovirus pneumonia.

Interleukin-6 (IL-6) is a pleiotropic cytokine that is a regulator of inflammation and immunity. As production of IL-6 may be an important mechanism by which local and systemic inflammatory processes are regulated during lung transplantation, we measured this cytokine concentration in the serum and bronchoalveolar lavage fluid (BALF) collected in 27 lung recipients. IL-6 bioactivity was analyzed using a B cell hybridoma proliferation assay (B9 cell line). Three groups of clinical situations were analyzed: control lung recipients, rejections, and CMV pneumonia. Serum IL-6 concentrations (mean +/- SEM) were 24.2 +/- 3.3 U/ml in the 26 control samples. In 20 allograft rejection episodes, the serum IL-6 concentration was higher than in control samples but the difference was not significant (59.3 +/- 20.5 U/ml, P > 0.05). IL-6 serum levels were significantly increased during the 14 CMV pneumonias (61.2 +/- 11.5 U/ml, P < 0.01). In BALF, IL-6 levels were increased during CMV pneumonia (52.4 +/- 21.9 U/ml BALF), and to a lesser extent during rejection events (14.1 +/- 3.7 U/ml BALF), as compared with controls (5.6 +/- 1.6 U/ml BALF, P < 0.005, and P < 0.05, respectively). Similar results were observed when IL-6/albumin and IL-6/urea ratios were determined so as to compensate for possible dilution effects in BALF. IL-6 in BALF was produced in situ during CMV pneumonia as shown by in situ hybridization experiments that revealed a significant number of IL-6 gene-expressing alveolar cells in this condition. IL-6 concentrations in the serum and in the BALF were compared. There was no correlation between serum and BALF IL-6 concentrations, showing that serum IL-6 levels do not accurately reflect intrapulmonary IL-6 levels do not accurately reflect intrapulmonary IL-6 production. Thus IL-6 is produced within lung transplants during CMV pneumonia, and to a lesser extent during allograft rejection.

Activation of macrophages and cytotoxic cells during cytomegalovirus pneumonia complicating lung transplantations.

The functional status of immune cells within human transplanted lungs was analyzed during cytomegalovirus (CMV) pneumonia complicating lung and heart-lung transplantations. The expression of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) genes is a marker for the activation of macrophages as is that of serine esterase B (SE-B) gene for cytotoxic cells. The levels of expression of these genes by bronchoalveolar lavage (BAL) cells were determined by in situ hybridization. Eight cases of CMV pneumonia were included in this study. BAL cells from either rejection episodes (eight cases) or control transplanted patients experiencing neither infection nor allograft rejection (eight cases) were analyzed in parallel. In the control patients, virtually no cells expressed the IL-1 beta, the IL-6, or the SE-B genes. In contrast, these three genes were all expressed in samples from patients with CMV pneumonia. IL-1 beta gene-expressing cells were abundant in all infected patients (mean +/- SEM: 898 +/- 449 positive cells per 10(4) cells, p less than 0.001, compared with those in control patients). IL-6 gene-expressing cells were less numerous (92 +/- 74 positive cells per 10(4) cells) and present in five of the eight cases of CMV pneumonia. Activated cytotoxic cells were detected in seven of the eight cases of CMV pneumonia (36.5 +/- 19 SE-B gene-expressing cells per 10(4) cells, p less than 0.001). During allograft rejections (eight cases) IL-1 beta gene-expressing cells were present in all but one patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased lung clearance of 99mTcDTPA in allograft lung rejection. The Paris-Sud Lung Transplant Group.

To investigate whether lung 99mTc-DTPA clearance is altered during allograft lung rejection, a group of four double lung and 24 heart-lung transplant patients was studied using serial measurement of the clearance rate of aerosolized 99mTc-DTPA (DTPA-Cl), in association with pulmonary function tests, bronchoalveolar lavage, and transbronchial lung biopsies. Using histologic diagnosis as a standard, we compared 56 episodes with normal lung histology to 32 episodes with allograft lung rejection. A control group of 20 healthy nonsmokers was used to define normal DTPA-Cl. In patients with normal lung histology, DTPA-Cl was higher than in control subjects (2.62 +/- 0.25 versus 1.20 +/- 0.12 %/min; p less than 0.001). In the episodes of allograft lung rejection, DTPA-Cl increased to 3.65 +/- 0.41 %/min (p less than 0.02) as compared with episodes of normal lung histology. The change in DTPA-Cl during allograft lung rejection was correlated (r = 0.3, p less than 0.01) with the increased percentage of lymphocytes in bronchoalveolar lavage (27.8 +/- 3.5% in rejection versus 19.9 +/- 2.2% in normal histology; p less than 0.02). Sensitivity and specificity of DTPA-Cl measurement in detecting lung rejection were 69 and 82%, respectively, versus 45 and 85% for FEV1 measurement. These results suggest that DTPA-Cl monitoring could be used in conjunction with pulmonary function testing as a noninvasive approach for the detection of lung rejection.

[Primary pulmonary artery hypertension (data of the literature and personal experience with 25 cases in 10 years)]. / Hypertension artérielle pulmonaire primitive (données de la littérature et expérience personnelle sur 125 cas en 10 ans).

Primary pulmonary hypertension (PPH) is an uncommon disease, of unknown cause. Patients are usually young with a slight predominance in females. We report our experience of 125 patients over 10 years and it is compared to the data of the literature. Epidemiology, physiopathology, clinical and hemodynamic features are reported. Therapeutic aspects are discussed, pointing out on more recent approaches like vasodilating drugs, lung and heart-lung transplantation. Prognosis and survival are presented.

[Nodular regenerative hyperplasia and pulmonary arterial hypertension]. / Hyperplasie nodulaire régénérative et hypertension artérielle pulmonaire.

Two cases of nodular regenerative hyperplasia of the liver coexisting with pulmonary hypertension are described. Regarding its low frequency, nodular regenerative hyperplasia has been found more often than expected in our series of coexisting porto-pulmonary hypertension (2 out of 14 cases, 14 percent). In our 2 cases, pulmonary symptoms occurred before or simultaneously with hepatic symptoms. The high prevalence of this association and the unusual onset setting of symptoms suggest that this association is unfortuitous. A common pathogenesis for pulmonary and hepatic lesions is discussed.

Early neutrophil alveolitis after rechallenge in drug induced alveolitis.

A patient with drug induced alveolitis due to an antidepressant drug, nomifensine, is described. After an inadvertent rechallenge by the patient sequential bronchoalveolar lavage was carried out. Twenty four hours after the rechallenge the lavage fluid contained a high cell count with neutrophils predominating. Seven days after challenge the cells were predominantly lymphocytes.