NGF increases Connexin-43 expression and function in pulmonary arterial smooth muscle cells to induce pulmonary artery hyperreactivity.

AIMS: Pulmonary hypertension (PH) is characterised by an increase in pulmonary arterial pressure, ultimately leading to right ventricular failure and death. We have previously shown that nerve growth factor (NGF) plays a critical role in PH. Our objectives here were to determine whether NGF controls Connexin-43 (Cx43) expression and function in the pulmonary arterial smooth muscle, and whether this mechanism contributes to NGF-induced pulmonary artery hyperreactivity. METHODS AND RESULTS: NGF activates its TrkA receptor to increase Cx43 expression, phosphorylation, and localization at the plasma membrane in human pulmonary arterial smooth muscle cells, thus leading to enhanced activity of Cx43-dependent GAP junctions as shown by Lucifer Yellow dye assay transfer and fluorescence recovery after photobleaching -FRAP- experiments. Using both in vitro pharmacological and in vivo SiRNA approaches, we demonstrate that NGF-dependent increase in Cx43 expression and activity in the rat pulmonary circulation causes pulmonary artery hyperreactivity. We also show that, in a rat model of PH induced by chronic hypoxia, in vivo blockade of NGF or of its TrkA receptor significantly reduces Cx43 increased pulmonary arterial expression induced by chronic hypoxia and displays preventive effects on pulmonary arterial pressure increase and right heart hypertrophy. CONCLUSIONS: Modulation of Cx43 by NGF in pulmonary arterial smooth muscle cells contributes to NGF-induced alterations of pulmonary artery reactivity. Since NGF and its TrkA receptor play a role in vivo in Cx43 increased expression in PH induced by chronic hypoxia, these NGF/Cx43-dependent mechanisms may therefore play a significant role in human PH pathophysiology.

Inflammation and Oxidative Stress Induce NGF Secretion by Pulmonary Arterial Cells through a TGF-ß1-Dependent Mechanism.

Expression of the nerve growth factor NGF is increased in pulmonary hypertension (PH). We have here studied whether oxidative stress and inflammation, two pathological conditions associated with transforming growth factor-ß1 (TGF-ß1) in PH, may trigger NGF secretion by pulmonary arterial (PA) cells. Effects of hydrogen peroxide (H2O2) and interleukin-1ß (IL-1ß) were investigated ex vivo on rat pulmonary arteries, as well as in vitro on human PA smooth muscle (hPASMC) or endothelial cells (hPAEC). TßRI expression was assessed by Western blotting. NGF PA secretion was assessed by ELISA after TGF-ß1 blockade (anti-TGF-ß1 siRNA, TGF-ß1 blocking antibodies, TßRI kinase, p38 or Smad3 inhibitors). TßRI PA expression was evidenced by Western blotting both ex vivo and in vitro. H2O2 or IL-1ß significantly increased NGF secretion by hPASMC and hPAEC, and this effect was significantly reduced when blocking TGF-ß1 expression, binding to TßRI, TßRI activity, or signaling pathways. In conclusion, oxidative stress and inflammation may trigger TGF-ß1 secretion by hPASMC and hPAEC. TGF-ß1 may then act as an autocrine factor on these cells, increasing NGF secretion via TßRI activation. Since NGF and TGF-ß1 are relevant growth factors involved in PA remodeling, such mechanisms may therefore be relevant to PH pathophysiology.

Connexin-43 is a promising target for pulmonary hypertension due to hypoxaemic lung disease.

The mechanisms underlying pulmonary hypertension (PH) are complex and multifactorial, and involve different cell types that are interconnected through gap junctional channels. Although connexin (Cx)-43 is the most abundant gap junction protein in the heart and lungs, and critically governs intercellular signalling communication, its contribution to PH remains unknown. The focus of the present study is thus to evaluate Cx43 as a potential new target in PH.Expressions of Cx37, Cx40 and Cx43 were studied in lung specimens from patients with idiopathic pulmonary arterial hypertension (IPAH) or PH associated with chronic hypoxaemic lung diseases (chronic hypoxia-induced pulmonary hypertension (CH-PH)). Heterozygous Cx43 knockdown CD1 (Cx43+/-) and wild-type littermate (Cx43+/+) mice at 12 weeks of age were randomly divided into two groups, one of which was maintained in room air and the other exposed to hypoxia (10% oxygen) for 3 weeks. We evaluated pulmonary haemodynamics, remodelling processes in cardiac tissues and pulmonary arteries (PAs), lung inflammation and PA vasoreactivity.Cx43 levels were increased in PAs from CH-PH patients and decreased in PAs from IPAH patients; however, no difference in Cx37 or Cx40 levels was noted. Upon hypoxia treatment, the Cx43+/- mice were partially protected against CH-PH when compared to Cx43+/+ mice, with reduced pulmonary arterial muscularisation and inflammatory infiltration. Interestingly, the adaptive changes in cardiac remodelling in Cx43+/- mice were not affected. PA contraction due to endothelin-1 (ET-1) was increased in Cx43+/- mice under normoxic and hypoxic conditions.Taken together, these results indicate that targeting Cx43 may have beneficial therapeutic effects in PH without affecting compensatory cardiac hypertrophy.

No compensatory lung growth after resection in a one-year follow-up cohort of patients with lung cancer.

BACKGROUND: As compensatory lung growth after lung resection has been studied in animals of various ages and in one case report in a young adult, it has not been studied in a cohort of adults operated for lung cancer. METHODS: A prospective study including patients with lung cancer was conducted over two years. Parenchymal mass was calculated using computed tomography before (M0) and at 3 and 12 months (M3 and M12) after surgery. Respiratory function was estimated by plethysmography and CO/NO lung transfer (DLCO and DLNO). Pulmonary capillary blood volume (Vc) and membrane conductance for CO (DmCO) were calculated. Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) plasma concentrations were measured simultaneously. RESULTS: Forty-nine patients underwent a pneumonectomy (N=12) or a lobectomy (N=37) thirty two completed the protocol. Among all patients, from M3 to M12 the masses of the operated lungs (239±58 to 238±72 g in the lobectomy group) and of the non-operated lungs (393±84 to 377±68 g) did not change. Adjusted by the alveolar volume (VA), DLNO/VA decreased transiently by 7% at M3, returning towards the M0 value at M12. Both Vc and DmCO increased slightly between M3 and M12. IGF-1 and IGFBP-3 concentrations did not change at M3, IGF-1 decreased significantly from M3 to M12. CONCLUSIONS: Compensatory lung growth did not occur over one year after lung surgery. The lung function data could suggest a slight recruitment or distension of capillaries owing to the likely hemodynamic alterations. An angiogenesis process is unlikely.

Video-axillaroscopy: a new mini-invasive technique for surgical exploration of the axillary region.

Subclavicular lymph nodes are one of the deeper lymph node groups of the lymphatic network located in the axillary region. As its location is surrounded by vessels and nerves, biopsy of subclavicular lymph nodes is not possible without eye control. We describe a new, mini-invasive technique for accessing the thoracic outlet region. Video-axillaroscopy is a reliable mini-invasive technique for targeting biopsies of lymph nodes in the axillary region. It is safer and more accurate than radio-guided techniques. Exploration of this region might benefit treatment of lymphoma and breast cancer and applications might emerge for thoracic outlet syndromes.

Transaortic migration of a Steinman wire from the shoulder.

Orthopedic pins and wires are regularly used for the treatment of bone fractures and dislocations. Migration of these devices from the shoulder into the thoracic cavity is an uncommon but well-known complication. However, great vessels' injuries by a migrated wire are extremely rare. We report the case of a 78-year-old woman with a penetrating injury of the ascending thoracic aorta and the superior vena cava caused by migration of a Steinman wire that was used for percutaneous fixation of a left-shoulder dislocation 5 years earlier. There was no hemothorax, hemomediastinum, or hemopericardia, but hemoptysis was present. Such a case has not been previously described. The patient was treated by an emergency median sternotomy with a favorable outcome.

Early complications after pneumonectomy: retrospective study of 168 patients.

The purpose of this study was to assess the mortality and risk factors of complications after pneumonectomy for lung cancer. Between 1996 and 2001, we reviewed and analysed the demographic, clinical, functional, and surgical variables of 168 patients to identify risk factors of postoperative complications by univariate and multivariate analyses with Medlog software system. The mean age was 60+/-10 years, overall mortality and morbidity rates were 4.17% and 41.6%, respectively. All frequencies of respiratory complications were 1.2% for acute respiratory failure, 10.1% for pneumonia, 2.4% for acute pulmonary oedema, 4.17% for bronchopleural fistula, 2.4% for thoracic empyema and 18.5% for left recurrent nerve injuries. Postoperative arrhythmias developed in 46% of our patients. The risk factors for cardiopulmonary morbidity and mortality with univariate analysis were advanced age (P<0.01), preoperative poor performance status (P<0.015), and chronic artery disease (P<0.008). Factors adversely affecting morbidity with multivariate analysis included age (P=0.0001), associated cardiovascular disease (P=0.001), and altered forced expiratory volume in 1 s (P=0.0005). Complications after pneumonectomy are associated with high mortality. Careful attention must be paid to patients with advanced age and heart disease. Chest physiotherapy is paramount to have uneventful outcomes.

The hemiclamshell approach in thoracic surgery: indications and associated morbidity in 50 patients.

This retrospective study was carried out to evaluate the indications for and outcomes of the hemiclamshell (HCS) approach (longitudinal partial sternotomy with antero-lateral thoracotomy) in patients undergoing mass resection in thoracic surgery. All patients (50) who underwent a HCS procedure in our department, between July 1996 and July 2005, were studied retrospectively, analyzing the indications, morbidity and outcome (pain, neurological or shoulder defects, mortality) at one month and one year. The main indications were apical tumours (38%), tumours of the cervicothoracic junction (46%) and chest wall (10%), and 'bulky' tumours (6%). One-month mortality was 6%. Two patients suffered from a chylothorax and one from phrenic paralysis. The postoperative analgesic requirements were similar to those after other thoracic surgery approaches. Twelve percent of patients suffered pain at one month and 6% at one year. Shoulder dysfunction was observed in 10% of patients at one month and 6% at one year. In conclusion, the HCS surgical approach was associated with an uncomplicated postoperative course. This anterior approach is suitable for apical tumours, tumours of the cervicothoracic junction and 'bulky' lung tumours, providing good access for control of the large vessels and radical mediastinal clearance.

Combination of surgical and endoscopic approach for Zenker's diverticulum.

A simple technique to improve external surgical treatment of Zenker's diverticulum is presented. A rigid esophageal endoscopy is performed just before the operation. The diverticulum is explored and washed. A single lumen tracheal tube is inserted into the esophageal lumen to serve as a stent. The technique is safe and easy and improves the bacterial control of the operation field.

Primary esophageal repair for Boerhaave's syndrome whatever the free interval between perforation and treatment.

OBJECTIVES: Boerhaave's syndrome is the most sinister cause of esophageal perforation responsible with mortality rate ranging from 20 to 30%. Combination of mediastinal contamination with microorganisms, gastric acid and digestives enzymes, long free interval between injury and initiation of treatment causes severe mediastinitis which is fatal in most untreated cases. The aim of this paper is to emphasize primary esophageal repair and resuscitation whatever the free interval from rupture and repair. METHODS: A retrospective review of patients treated for Boerhaave's syndrome in our department from January 1980 to February 2003 was performed. The principle of treatment was surgical treatment and avoidance of esophageal exclusion or esophagectomy whichever was possible. RESULTS: There were 25 patients (17 males and 8 females). All patients were operated on by primary esophageal repair, except for three who underwent immediate exclusion of the esophagus and one patient who deceased on arrival before being operated. Patients were classified according to free interval between perforation and treatment: group 1 (n=9; 36%) within the 24 h (range from 12 to 24 h) and group 2 (n=16; 64%) more than 24 h (range from 2 to 17 days). Altogether 6 patients deceased (24%). In hospital mortality rate for groups 1 and 2 was, respectively, 44% (four patients) and 13% (two patients), not significantly different. Mean hospital stay was 63 days. Two patients developed anastomotic leakage needing esophagectomy and retrosternal coloplasty in one or more steps. One patient developed pleural abscess treated by percutaneous drainage. Three patients presented temporary symptomatic esophageal stenosis, of whom one underwent dilation. CONCLUSIONS: Long free interval before treatment does not preclude primary esophageal repair in Boerhaave's syndrome. Esophageal exclusion may be more often than not avoided in most cases.

Assessment of spontaneous pneumomediastinum: experience with 12 patients.

BACKGROUND: The aim of this study is to report a series of spontaneous pneumomediastinum in a population of young, tall, and thin patients with a history of thoracic hyper pressure, and to analyze the assessment required in such patients. METHODS: A retrospective study of an unicentric series and a review of the literature from 1980 to 2002 were performed. RESULTS: Between December 1996 and January 2002, 12 patients (mean age, 25 years old; mean height, 172 cm; and mean weight, 63 kg) were admitted with spontaneous pneumomediastinum. In all patients, high intrathoracic pressure by cough or acute effort was the precipitating factor. Most frequent complaints were acute chest pain, asthenia, and subcutaneous emphysema. The following assessment was performed: chest roentgenogram in 12 of 12 patients (12/12); computer tomography (CT) scan in 8/12; bronchoscopy in 7/12; esophagoscopy in 6/12; esophagography in 2/12. Outcome was always uneventful without any recurrence. Hospital stay ranged from 0 to 6 days. The Medline research revealed that articles consist mainly of case reports. Two articles only report a multicentric series of 25 and 36 cases, respectively. No organ perforation was found either in our series or in our review of the literature. CONCLUSIONS: Spontaneous pneumomediastinum follows alveolar rupture in the pulmonary interstitium. The dissection of gas towards the hilum and mediastinum is produced by an episode of acute high intrathoracic pressure. It affects mostly young people, and this is the case in our series. Endoscopic thoracic assessment may be risky and is not always necessary. Chest CT or esophageal contrast study should be performed in case of diagnostic doubt of esophageal perforation.

Massive hemoptysis: what place for medical and surgical treatment.

OBJECTIVE: The objective of the study was to define timing of surgical treatment in management of massive hemoptysis. METHODS: We performed a retrospective review of all patients admitted for massive hemoptysis in the intensive care unit of our thoracic surgery department. Treatment was managed according to the patient's status, the etiology of bleeding, the findings of bronchoscopy and computed tomographic scan. Therapeutic measures available were medical treatment, tracheal intubation (single or double lumen tube), interventional endoscopy, arterial embolisation and surgical treatment. RESULTS: Between September 1996 and December 2001, 43 patients were treated (nine females and 34 males with mean age of 54 years, range from 32 to 79). The mean red cell blood transfusion per patient was 1.57 Units. The patients were classified into three groups: Group 1, 11 patients were operated on immediately close to the bleeding crise (five pneumonectomy and six lobectomy); Group 2, five patients for whom operation was delayed from the 7th to the 22nd day after cessation of bleeding (five lobectomy); Group 3, 27 patients were treated by non-surgical methods (medical treatment, endobronchial treatment, percutaneous embolisation). Fifteen patients underwent an arterial embolization, which was complete in 13 cases. Among the five patients of group 2, cessation of bleeding was obtained by bronchial embolisation in four cases. Considering the whole series, 10 (23%) patients died: three (19%) patients in group 1, zero in group 2, seven (26%) in group 3. In two patients who were suffering from tumor necrosis, hemoptysis relapsed leading to death. CONCLUSION: Emergency thoracotomy for massive hemoptysis is at high risk. In case of bleeding from the arterial bronchial vessels, embolization may enable to postpone surgery and operate secondarily. In case of bleeding from the pulmonary vessels (tumor necrosis), surgical treatment must be immediate. An algorithm for management is proposed.