Tiago Henriques-Coelho

Transvesical thoracoscopy: A natural orifice translumenal endoscopic approach for thoracic surgery

BackgroundRecently there has been an increasing enthusiasm for using natural orifices translumenal endoscopic surgery (NOTES) to perform scarless abdominal procedures. We have previously reported the feasibility and safety of the transvesical endoscopic peritoneoscopy in a long-term survival porcine model as useful for those purposes. Herein, we report our successful experience performing transvesical and transdiaphragmatic endoscopic approach to the thoracic cavity in a long-term survival study in a porcine model.MethodsTransvesical and transdiaphragmatic endoscopic thoracoscopy was performed in six anesthetized female pigs. A 5 mm transvesical port was created on the bladder wall and an ureteroscope was advanced into the peritoneal cavity. After diaphragm inspection, we introduced through the left diaphragmatic dome a ureteroscope into the left thoracic cavity. In all animals, we performed thoracoscopy as well as peripheral lung biopsy. Animals were sacrificed by day 15 postoperatively.ResultsWe easily introduced a 9.8 Fr ureteroscope into the thoracic cavity that allowed us to visualize the pleural cavity and to perform simple surgical procedures such as lung biopsies without complications. There were neither respiratory distress episodes nor surgical complications to report. Postmortem examination revealed complete healing of vesical and diaphragmatic holes, whereas no signs of infection or adhesions were observed in the peritoneal or thoracic cavities.ConclusionThis study demonstrates the feasibility of transvesical thoracoscopy in porcine model. However, although this study extends the potential applications of NOTES to the thoracic cavity, new instruments and further work are needed to provide evidence that this could be translated to humans and with advantages for patients.

Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension

We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 microg*kg(-1)*day(-1) ip) or a similar volume of saline, resulting in four groups: sham (n = 11), sham-AP (n = 11), MCT (n = 16), and MCT-AP (n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 +/- 38%), diameter of cardiomyocyte (40 +/- 10%), myocardial fibrosis (95 +/- 20%), peak systolic pressure (99 +/- 22%), peak rate of ventricular pressure rise (dP/dt(max); 74 +/- 24%), peak rate of ventricular pressure decline (dP/dt(min); 73 +/- 19%), and time constant tau (55 +/- 16%). In these animals, RV expression of apelin (-73 +/- 10%) and its receptor APJ (-61 +/- 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 +/- 713%), angiotensinogen (191 +/- 147%), endothelin-1 (RV, 497 +/- 156%; and LV, 799 +/- 309%), plasmatic levels of apelin (104 +/- 48%), and angiotensin 1-7 (161 +/- 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

Cystic Adenomatoid Malformations Are Induced by Localized FGF10 Overexpression in Fetal Rat Lung

Fibroblast growth factor-10 (FGF10) is a mesenchymal growth factor, involved in epithelial and mesenchymal interactions during lung branching morphogenesis. In the present work, FGF10 overexpression was transiently induced in a temporally and spatially restricted manner, during the pseudoglandular or canalicular stages of rat lung development, by trans-uterine ultrasound-guided intraparenchymal microinjections of adenoviral vector encoding the rfgf10 transgene. The morphologic and histologic classification of the resulting malformations were dependent upon developmental stage and location. Overexpression of FGF10 restricted to the proximal tracheobronchial tree during the pseudoglandular phase resulted in large cysts lined by tall columnar epithelium composed primarily of Clara cells with a paucity of Type II pneumocytes, resembling bronchiolar type epithelium. In contrast, FGF10 overexpression in the distal lung parenchyma during the canalicular phase resulted in small cysts lined by cuboidal epithelial cells composed of primarily Type II pneumocytes resembling acinar epithelial differentiation. The cystic malformations induced by FGF10 overexpression appear to closely recapitulate the morphology and histology of the spectrum of human congenital cystic adenomatoid malformation (CCAM). These findings support a role for FGF10 in the induction of human CCAM and provide further mechanistic insight into the role of FGF10 in normal and abnormal lung development.

Current pathophysiological concepts and management of pulmonary hypertension

Pulmonary hypertension (PH), increasingly recognized as a major health burden, remains underdiagnosed due mainly to the unspecific symptoms. Pulmonary arterial hypertension (PAH) has been extensively investigated. Pathophysiological knowledge derives mostly from experimental models. Paradoxically, common non-PAH PH forms remain largely unexplored. Drugs targeting lung vascular tonus became available during the last two decades, notwithstanding the disease progresses in many patients. The aim of this review is to summarize recent advances in epidemiology, pathophysiology and management with particular focus on associated myocardial and systemic compromise and experimental therapeutic possibilities. PAH, currently viewed as a panvasculopathy, is due to a crosstalk between endothelial and smooth muscle cells, inflammatory activation and altered subcellular pathways. Cardiac cachexia and right ventricular compromise are fundamental determinants of PH prognosis. Combined vasodilator therapy is already mainstay for refractory cases, but drugs directed at these new pathophysiological pathways may constitute a significant advance.

Endoscopic Closure of Transmural Bladder Wall Perforations

BACKGROUND Traditionally, intraperitoneal bladder perforations caused by trauma or iatrogenic interventions have been treated by open or laparoscopic surgery. Additionally, transvesical access to the peritoneal cavity has been reported to be feasible and useful for natural orifice translumenal endoscopic surgery (NOTES) but would be enhanced by a reliable method of closing the vesicotomy. OBJECTIVE To assess the feasibility and safety of an endoscopic closure method for vesical perforations using a flexible, small-diameter endoscopic suturing kit in a survival porcine model. DESIGN, SETTING, AND PARTICIPANTS This pilot study was performed at the University of Minho, Braga, Portugal, using six anesthetized female pigs. INTERVENTIONS Closure of a full-thickness longitudinal incision in the bladder dome (up to 10 mm in four animals and up to 20 mm in two animals) with the endoscopic suturing kit using one to three absorbable stitches. MEASUREMENTS The acute quality of sealing was immediately tested by distending the bladder with methylene-blue dye under laparoscopic control (in two animals). Without a bladder catheter, the animals were monitored daily for 2 wk, and a necropsy examination was performed to check for the signs of peritonitis, wound dehiscence, and quality of healing. RESULTS AND LIMITATIONS Endoscopic closure of bladder perforation was carried out easily and quickly in all animals. The laparoscopic view revealed no acute leak of methylene-blue dye after distension of the bladder. After recovery from anaesthesia, the pigs began to void normally, and no adverse event occurred. Postmortem examination revealed complete healing of vesical incision with no signs of infection or adhesions in the peritoneal cavity. No limitations have yet been studied clinically. CONCLUSIONS This study demonstrates the feasibility and the safety of endoscopic closure of vesical perforations with an endoscopic suturing kit in a survival porcine model. This study provides support for further studies using endoscopic closure of the bladder which may lead to a new era in management of bladder rupture and adoption of the transvesical port in NOTES procedures.

Inotropic and lusitropic effects of ghrelin and their modulation by the endocardial endothelium, NO, prostaglandins, GHS-R1a and KCa channels.

Contractile effects of ghrelin (10(-9) to 10(-6) M) were tested in rat papillary muscles of normal (n = 50) and hypertrophic (n = 16) right ventricles (RV). RV hypertrophy was induced by pulmonary hypertension using monocrotaline. In normal muscles, ghrelin was added either alone (n = 9) or after pre-treatment with indomethacin (cycloxygenase inhibitor, 10(-5) M; n = 10), L-nitro-L-arginin (NO synthase inhibitor, 10(-4) M; n = 9), D-Lys(3)-GHRP-6 (GHS-R1a antagonist; 10(-4) M; n = 8) or apamin+charybdotoxin (KCa channels blockers; 10(-6) M, n =7 ), as well as after damaging the endocardial endothelium (n = 7). In hypertrophic muscles, ghrelin was added either alone (n = 9) or after pre-treatment with apamin+charybdotoxin (10(-6 M, n=7). Ghrelin concentration-dependently decreased active tension (AT) and maximal velocity of tension rise (negative inotropic effect), as well as, maximal velocity of tension decay (negative lusitropic effect) and time to AT (onset of relaxation). These effects were maximal at 10(-6) M, similar in normal and hypertrophic muscles and were significantly altered only by apamin+charybdotoxin, indomethacin and L-nitro-L-arginin. Apamin+charybdotoxin attenuated the negative inotropic effect, while indomethacin and L-nitro-L-arginin, respectively, blunted and exacerbated the premature onset of relaxation. In conclusion, ghrelin induces negative inotropic and lusitropic effects and an earlier onset of relaxation in normal and hypertrophic myocardium, which are independent of GHS-R1a, since they were not affected by D-Lys(3)-GHRP-6. The negative inotropic effect is partly mediated by KCa channels, while the earlier onset of relaxation is modulated by prostaglandins and NO.

Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia

Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endocrine actions. In this study, ghrelin expression in humans and rats was evaluated throughout development of normal and hypoplastic lungs associated with congenital diaphragmatic hernia (CDH). Additionally, the effect of antenatal treatment with ghrelin in the nitrofen-induced CDH rat model was tested. In normal lungs, ghrelin was expressed in the primitive epithelium at early stages of development and decreased in levels of expression with gestational age. In hypoplastic lungs ghrelin was overexpressed in both human and rat CDH fetuses when compared with controls. Exogenous administration of ghrelin to nitrofen-treated dams led to an attenuation of pulmonary hypoplasia of CDH pups. Furthermore, the growth hormone, secretagogue receptor (GHSR1a), could not be amplified from human or rat fetal lungs by RT-PCR. In conclusion, of all the lungs studied so far, the fetal lung is one of the first to express ghrelin during development and might be considered a new source of circulating fetal ghrelin. Overexpression of ghrelin in hypoplastic lungs and the effect of exogenous administration of ghrelin to nitrofen-treated dams strongly suggest a role for ghrelin in mechanisms involved in attenuation of fetal lung hypoplasia, most likely through a GHSR1a-independent pathway.

Thymulin inhibits monocrotaline-induced pulmonary hypertension modulating interleukin-6 expression and suppressing p38 pathway

The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zinc-dependent thymic hormone, has important immunobiological effects by inhibiting various proinflammatory cytokines and chemokines. We investigated morphological and hemodynamic effects of thymulin administration in a rat model of monocrotaline (MCT)-induced PH, as well as the pattern of proinflammatory cytokine gene expression and the intracellular pathways involved. Adult Wistar rats received an injection of MCT (60 mg/kg, sc) or an equal volume of saline. One day after, the animals randomly received during 3 wk an injection of saline, vehicle (zinc plus carboxymethyl cellulose), or thymulin (100 ng/kg, sc, daily). At d 23-25, the animals were anesthetized for hemodynamic recordings, whereas heart and lungs were collected for morphometric and molecular analysis. Thymulin prevented morphological, hemodynamic, and inflammatory cardiopulmonary profile characteristic of MCT-induced PH, whereas part of these effects were also observed in MCT-treated animals injected with the thymulins vehicle containing zinc. The pulmonary thymulin effect was likely mediated through suppression of p38 pathway.

Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach.

Pulmonary arterial hypertension (PAH) is responsible for the premature death mainly because of progressive and severe heart failure. This disease is characterized by increased pulmonary vascular tone, inflammatory cell infiltration, vascular remodeling and occlusion of vessels with thrombi, frequently leading to right heart failure. Aiming to better comprehend the complexity of PAH and find novel therapeutic strategies or improve the existing ones, a variety of preclinical models have emerged. Although there is no ideal preclinical model of PAH currently available, animal models have been used to assist in the identification of the molecular pathways underlying PAH development and progression, and in the identification of novel therapeutics. Among preclinical models of PAH, monocrotaline (MCT) animal model offers the advantage of mimic several key aspects of human PAH, including vascular remodeling, proliferation of smooth muscle cells, endothelial dysfunction, upregulation of inflammatory cytokines, and right ventricle failure, requiring a single drug injection. This review summarizes the advantages and limitations of MCT animal model to the study of the molecular mechanisms underlying PAH pathogenesis, envisioning to improve the diagnosis and management of this complex disease.

Prenatal and Postnatal Management of Congenital Pulmonary Airway Malformation

Congenital pulmonary airway malformation (CPAM) is one of the most common lung lesions detected prenatally. Despite the research efforts made in the past few years, controversy and lack of clarity in the literature still exist regarding nomenclature, classification, pathogenesis and the management of CPAM. Therefore, it is of greatest importance to delineate the natural history of CPAMs and to create a consensus to guide the management and follow-up of these lesions. This review will focus on classification systems, highlighting the most recent advancements in pathogenesis, and current practice in the prenatal diagnosis of CPAM. Strategies of prenatal management and postnatal management will be reviewed. Long-term follow-up, including lung cancer risk, is discussed and an outcome perspective is presented.