Electronic Nicotine Delivery Systems (ENDS) are methods of delivering nicotine without combustion, which happens in cigarettes. These devices consist of a heating element, a battery, and a tank which stores eliquid. Over the years these devices have become more powerful, and capable of increased delivery of nicotine. There is a large variety of flavors and devices, which causes trouble for standardized studies. These devices were created to help cigarette users quit smoking; however, they are associated with significant dual use. ENDS produce lower levels of most toxic chemicals when compared to cigarettes, and significantly increased levels when compared to not smoking. Newer generation ENDS have capabilities of producing levels of reactive oxygen species and carbonyl compounds at levels similar to cigarettes. ENDS use has detrimental effects on the genome, immune system, and lung function due to exposure from these chemicals. These effects are at lower levels when compared to cigarette use. Chronic ENDS use has been associated with chronic obstructive pulmonary disorder (COPD), with an even higher association with dual use. ENDS use also causes DNA adduct formation, and activates protein kinases, nicotine acetylcholine receptors and other pathways for lung cancer as cigarette use. The full health effects of ENDS use are still unknown, from the currents studies it is clear that its use is not without harm.

A sinalização por endocanabinóides é finalizada por meio de hidrólise enzimática; um processo que para o endocanabinóide 2-Arachidonoylglycerol (2-AG) é mediado pela lipase monoacilglicerol (MAGL). O JZL184, é um fármaco que apresenta alta seletividade na inibição da MAGL. Assim, o JZL184 aumenta os níveis de 2-AG que, por sua vez, atua sobre os receptores canabinóides CB1 e CB2 produzindo diversos efeitos como, por exemplo, o anti-inflamatório. A inflamação pulmonar aguda (ALI) e a sua forma mais grave, a síndrome do desconforto respiratório agudo (SDRA), em humanos, são doenças pulmonares, caracterizadas por infiltrado pulmonar bilateral com acúmulo de neutrófilos. A sepse é a causa mais comum da ALI/SDRA; aproximadamente 40% de pacientes com sépsis, também apresentam ALI ou ARDS e a ALI/ARDS são síndromes graves associadas com mortalidade superior a 40%. Considerando que não há cura para a ARDS / ALI, foi utilizado um modelo murino de ALI para averiguar se a inibição da MAGL seria capaz de aliviar os sintomas inflamatórios ou, até mesmo, promover a cura do processo. Para isso, foram analisados fatores que promovem a migração de leucócitos para o pulmão e o dano tecidual. Ainda, para avaliar se os LPS e/ou o JZL184 promoveram mudanças no sistema nervoso central, foram avaliados a atividade locomotora no campo aberto (CA), a ansiedade no labirinto (LCE), a capacidade de adaptação em CA e os níveis de glicocorticóides séricos, assim como os níveis hipotalâmicos de citocinas. Assim, o JZL184, foi administrado por via intraperitoneal (i.p.) e 60 minutos depois o LPS foi instilado por via intranasal. As análises foram realizadas 6, 24 e/ou 48 horas após a indução da ALI. Observou-se que a inibição MAGL diminuiu a migração de leucócitos para os pulmões, bem como a permeabilidade vascular e o dano tecidual. O JZL184 também reduziu os níveis de citocinas e quimiocinas e o extravasamento vascular no lavado bronco alveolar (LBA), a atividade de MPO no tecido pulmonar e a expressão da molécula de adesão no sangue e no LBA. Os receptores CB1 e CB2 foram considerados como envolvidos nos efeitos anti-inflamatórios produzidos pelo JZL184 porque o AM281, um antagonista seletivo do receptor CB1, e o AM630, um antagonista seletivo do receptor CB2, reduziram ou bloquearam os efeitos anti-inflamatórios para JZL184. O LPS e o JZL184 não promoveram comportamento doentio e tampouco alteraram os parâmetros de ansiedade. Entretanto, o LPS e/ou o JZL184 aumentaram a expressão gênica de citocinas hipotalâmicas. Concluiu-se que a inibição MAGL produziu efeitos anti-inflamatórios no modelo murino de ALI induzida por LPS, uma descoberta que foi considerada uma consequência da ativação dos receptores canabinóide CB1 e CB2. A inibição da MAGL pode ser, no futuro, uma ferramenta terapêutica relevante para o tratamento de inflamações pulmonares / Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG), is mediated by monoacylglycerol lipase (MAGL). The JZL184, is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors, and has shown anti-inflammatory effects. Acute lung injury (ALI) and its most severe form the acute respiratory distress syndrome (ARDS), in humans, are lung diseases, characterized by bilateral pulmonary infiltrate with neutrophils accumulation. The sepsis is the most common cause of ALI / ARDS; approximately 40% of patients with sepsis have also ALI or ARDS. ALI and ARDS are severe syndromes associated with mortality 40% exceeding rates. Considering that there is no cure for ARDS/ALI, we used a ALI murine model to evaluate if the MAGL inhibition was able to alleviating the inflammatory symptoms or even promote the cure. For this, factors that promote migration of leukocytes into the lungs and the tissue damage were analyzed. Still, to assess whether LPS and / or JZL184 promoted changes in the central nervous system, the locomotor activity and ability to adapt were evaluated in the open field end the anxiety in the plus maze. Were also evaluated the glucocorticoid levels in the serum, and the hypothalamic levels of cytokines. Thus, the JZL184 was used intraperitoneally, 60 minutes after LPS was intranasally instilled and 6, 24 and/or 48 hours, after induction of ALI, analyzes were performed. It was observed that the MAGL inhibition decreased the leukocyte migration into the lungs as well as the vascular permeability and the lung damage. JZL184 also reduced the cytokine and chemokine levels and the vascular extravasation in the BAL, the MPO activity in the lungs and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281, a selective CB1 receptor antagonist, and the AM630, a selective CB2 receptor antagonist, reduced or blocked the anti-inflammatory effects previously described for JZL184. The LPS and the JZL184 did not promote unhealthy behavior and did not change the parameters of anxiety. However, LPS and/orJZL184 increased gene expression of hypothalamic cytokines. It was concluded that MAGL inhibition produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 cannabinoid receptors. The MAGL inhibition in the future may be a therapeutic tool for the pulmonary inflammation treatment

A sinalização por endocanabinóides é finalizada por meio de hidrólise enzimática; um processo que para o endocanabinóide 2-Arachidonoylglycerol (2-AG) é mediado pela lipase monoacilglicerol (MAGL). O JZL184, é um fármaco que apresenta alta seletividade na inibição da MAGL. Assim, o JZL184 aumenta os níveis de 2-AG que, por sua vez, atua sobre os receptores canabinóides CB1 e CB2 produzindo diversos efeitos como, por exemplo, o anti-inflamatório. A inflamação pulmonar aguda (ALI) e a sua forma mais grave, a síndrome do desconforto respiratório agudo (SDRA), em humanos, são doenças pulmonares, caracterizadas por infiltrado pulmonar bilateral com acúmulo de neutrófilos. A sepse é a causa mais comum da ALI/SDRA; aproximadamente 40% de pacientes com sépsis, também apresentam ALI ou ARDS e a ALI/ARDS são síndromes graves associadas com mortalidade superior a 40%. Considerando que não há cura para a ARDS / ALI, foi utilizado um modelo murino de ALI para averiguar se a inibição da MAGL seria capaz de aliviar os sintomas inflamatórios ou, até mesmo, promover a cura do processo. Para isso, foram analisados fatores que promovem a migração de leucócitos para o pulmão e o dano tecidual. Ainda, para avaliar se os LPS e/ou o JZL184 promoveram mudanças no sistema nervoso central, foram avaliados a atividade locomotora no campo aberto (CA), a ansiedade no labirinto (LCE), a capacidade de adaptação em CA e os níveis de glicocorticóides séricos, assim como os níveis hipotalâmicos de citocinas. Assim, o JZL184, foi administrado por via intraperitoneal (i.p.) e 60 minutos depois o LPS foi instilado por via intranasal. As análises foram realizadas 6, 24 e/ou 48 horas após a indução da ALI. Observou-se que a inibição MAGL diminuiu a migração de leucócitos para os pulmões, bem como a permeabilidade vascular e o dano tecidual. O JZL184 também reduziu os níveis de citocinas e quimiocinas e o extravasamento vascular no lavado bronco alveolar (LBA), a atividade de MPO no tecido pulmonar e a expressão da molécula de adesão no sangue e no LBA. Os receptores CB1 e CB2 foram considerados como envolvidos nos efeitos anti-inflamatórios produzidos pelo JZL184 porque o AM281, um antagonista seletivo do receptor CB1, e o AM630, um antagonista seletivo do receptor CB2, reduziram ou bloquearam os efeitos anti-inflamatórios para JZL184. O LPS e o JZL184 não promoveram comportamento doentio e tampouco alteraram os parâmetros de ansiedade. Entretanto, o LPS e/ou o JZL184 aumentaram a expressão gênica de citocinas hipotalâmicas. Concluiu-se que a inibição MAGL produziu efeitos anti-inflamatórios no modelo murino de ALI induzida por LPS, uma descoberta que foi considerada uma consequência da ativação dos receptores canabinóide CB1 e CB2. A inibição da MAGL pode ser, no futuro, uma ferramenta terapêutica relevante para o tratamento de inflamações pulmonares / Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG), is mediated by monoacylglycerol lipase (MAGL). The JZL184, is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors, and has shown anti-inflammatory effects. Acute lung injury (ALI) and its most severe form the acute respiratory distress syndrome (ARDS), in humans, are lung diseases, characterized by bilateral pulmonary infiltrate with neutrophils accumulation. The sepsis is the most common cause of ALI / ARDS; approximately 40% of patients with sepsis have also ALI or ARDS. ALI and ARDS are severe syndromes associated with mortality 40% exceeding rates. Considering that there is no cure for ARDS/ALI, we used a ALI murine model to evaluate if the MAGL inhibition was able to alleviating the inflammatory symptoms or even promote the cure. For this, factors that promote migration of leukocytes into the lungs and the tissue damage were analyzed. Still, to assess whether LPS and / or JZL184 promoted changes in the central nervous system, the locomotor activity and ability to adapt were evaluated in the open field end the anxiety in the plus maze. Were also evaluated the glucocorticoid levels in the serum, and the hypothalamic levels of cytokines. Thus, the JZL184 was used intraperitoneally, 60 minutes after LPS was intranasally instilled and 6, 24 and/or 48 hours, after induction of ALI, analyzes were performed. It was observed that the MAGL inhibition decreased the leukocyte migration into the lungs as well as the vascular permeability and the lung damage. JZL184 also reduced the cytokine and chemokine levels and the vascular extravasation in the BAL, the MPO activity in the lungs and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281, a selective CB1 receptor antagonist, and the AM630, a selective CB2 receptor antagonist, reduced or blocked the anti-inflammatory effects previously described for JZL184. The LPS and the JZL184 did not promote unhealthy behavior and did not change the parameters of anxiety. However, LPS and/orJZL184 increased gene expression of hypothalamic cytokines. It was concluded that MAGL inhibition produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 cannabinoid receptors. The MAGL inhibition in the future may be a therapeutic tool for the pulmonary inflammation treatment

The purpose of this study is to evaluate the value of systematic thoracic ultrasonography (TUS) for detecting bovine respiratory disease (BRD) related lung damage in Holstein x Angus crossbred calves. Because the dairy industry is known to operate on small profit margins, it is important to assess the potential of this technology to help prevent the main source of financial loss related to calf production that dairy producers face. Studies have shown that BRD may impact nearly a fourth of all dairy calves before weaning. In an industry that is currently growing and evolving, it is important that producers have all the necessary resources to operate efficiently. TUS is known to be a quick and accurate predictor of BRD related lung damage, but this study focuses on the financial implications of BRD related lung damage on calf growth and efficiency—average daily gain (ADG) and milk-to-gain (M:G)—and the value of implementing TUS information to make sound management decisions. TUS along with BRD diagnosis information give producers a unique perspective on future growth and development of calves and could be part of the solution to promote larger profit margins for dairy producers. We find that the value associated with TUS and BRD diagnosis information is between $0.88/head and $13.44/head and depends on BRD incidence rate, feed price, and feeder price. Depending on the cost to the farm, it may be beneficial to implement this as a way to manage BRD damage, which we know to influence calf growth and efficiency.

In experimental acute respiratory distress syndrome (ARDS), random variation of tidal volumes (VT ) during volume controlled ventilation improves gas exchange and respiratory system mechanics (so-called stochastic resonance hypothesis). It is unknown whether those positive effects may be further enhanced by periodic VT fluctuation at distinct frequencies, also known as deterministic frequency resonance.We hypothesized that the positive effects of variable ventilation on lung functionmay be further amplified by periodic VT fluctuation at specific frequencies. In anesthetized and mechanically ventilated pigs, severe ARDS was induced by saline lung lavage and injurious VT (double-hit model). Animals were then randomly assigned to 6 h of protective ventilation with one of four VT patterns: (1) random variation of VT (WN); (2) P04, main VT frequency of 0.13Hz; (3) P10, main VT frequency of 0.05Hz; (4) VCV, conventional non-variable volume controlled ventilation. In groups with variable VT , the coefficient of variation was identical (30%). We assessed lung mechanics and gas exchange, and determined lung histology and inflammation. Compared to VCV, WN, P04, and P10 resulted in lower respiratory system elastance (63 ± 13 cm H2O/L vs. 50 ± 14 cm H2O/L, 48.4 ± 21 cm H2O/L, and 45.1 ± 5.9 cm H2O/L respectively, P < 0.05 all), but only P10 improved PaO2/FIO2 after 6 h of ventilation (318 ± 96 vs. 445 ± 110mm Hg, P < 0.05). Cycle-by-cycle analysis of lung mechanics suggested intertidal recruitment/de-recruitment in P10. Lung histologic damage and inflammation did not differ among groups. In this experimental model of severe ARDS, periodic VT fluctuation at a frequency of 0.05Hz improved oxygenation during variable ventilation, suggesting that deterministic resonance adds further benefit to variable ventilation.

Le syndrome de détresse respiratoire aiguë (SDRA) est une forme de défaillance respiratoire sévère, cause majeure de mortalité (~30-45%) chez les adultes et enfants dans les unités de soins intensifs. En dépit des progrès dans la prise en charge du patient, il n’existe à ce jour aucun traitement curatif pharmacologique efficace. Le SDRA peut se développer à la suite d’une atteinte pulmonaire directe (ex. pneumonie) ou indirecte (ex. septicémie) dont les principales caractéristiques sont des lésions épithéliales alvéolaires et endothéliales vasculaires, le développement d’un oedème pulmonaire et une réponse inflammatoire exacerbée durant la phase aiguë exsudative. La résolution de ces paramètres est critique afin d’éviter l’établissement irréversible de fibrose, entraînant une défaillance respiratoire. Le caractère hétérogène du SDRA et l’implication d’une multitude de mécanismes lésionnels rendent le développement de nouvelles thérapies plus difficile. Nous avons posé l’hypothèse que la restauration de l’intégrité épithéliale, en parallèle de la résolution de l’inflammation et la résorption de l’oedème, est critique pour la résolution de la phase exsudative du SDRA. Nous avons donc postulé que des stratégies combinant des effets bénéfiques sur la clairance liquidienne et proréparatrice constitueraient une voie intéressante pour la restauration de l’intégrité fonctionnelle de l’épithélium alvéolaire. L’objectif général de mon projet de doctorat était donc d’évaluer différentes stratégies, ciblant 1) l’inflammation, 2) le canal sodique ENaC impliqué dans la clairance liquidienne et 3) les canaux potassiques ayant un rôle pro-réparateur, avec des modèles complémentaires in vivo de lésions aiguës induites, mimant des paramètres de SDRA. Nous pensons que cette étude aura apporté de nouvelles connaissances sur la physiopathologie du SDRA et les mécanismes de résolution des paramètres caractéristiques de ce syndrome. Mon projet met particulièrement en lumière que de cibler une seule composante telle que l’inflammation ou la clairance liquidienne n’est pas suffisante et que des composés permettant de restaurer l’intégrité fonctionnelle alvéolaire sont nécessaires. / Acute respiratory distress syndrome (ARDS) is a severe form of respiratory failure, a leading cause of death (~30-45%) among adults and children in intensive care units. Despite advances in the management and care of ARDS patients, there is currently no effective curative pharmacological treatment. The ARDS can develop following a direct (e.g. pneumonia) or indirect (e.g. sepsis) lung injury, the main features of which are alveolar epithelial and endothelial vascular injury, the development of pulmonary edema, and an exacerbated inflammatory response during the exsudative acute phase. The resolution of these parameters is critical to avoid the irreversible establishment of fibrosis leading to respiratory failure. The heterogeneous nature of ARDS and the involvement of various lesional mechanisms complicate the development of new therapeutic strategies. We hypothesized that the epithelial restoration, in parallel with inflammatory resolution and edema resorption, is critical for the resolution of the acute exsudative phase of ARDS. Therefore, we postulated that strategies combining beneficial effects on fluid clearance and pro repair may be an interesting way to restore the functional integrity of the alveolar epithelium. The general objective of my PhD project was to evaluate different strategies targeting 1) the inflammation, 2) the sodium channel ENaC involved in fluid clearance, and 3) potassium channels playing pro repair role, using complementary in vivo models of acute lung injury mimicking ARDS parameters. We believe that these studies have provided new insight on the pathophysiology of ARDS and the mechanisms of resolution of the characteristic parameters of this syndrome. In particular, my project highlights that focusing on a single component such as inflammation or fluid clearance is not sufficient and that compounds will restore functional alveolar integrity are needed.