American journal of respiratory and critical care medicine
-
Am. J. Respir. Crit. Care Med. · Feb 2014
Comparative StudymiR-199a-5p Silencing Regulates the Unfolded Protein Response in COPD and α1 Antitrypsin Deficiency.
Retention of abnormal α1-antitrypsin (AAT) activates the unfolded protein response in AAT-deficient monocytes. The regulatory role of microRNAs (miRNAs) in unfolded protein responses and chronic obstructive pulmonary disease pathogenesis has not been investigated. ⋯ miR-199a-5p is a key regulator of the unfolded protein response in AAT-deficient monocytes, and epigenetic silencing of its expression regulates this process in chronic obstructive pulmonary disease.
-
Am. J. Respir. Crit. Care Med. · Feb 2014
Regulation of Hypoxia-Induced Pulmonary Hypertension by Vascular Smooth Muscle HIF-1alpha.
Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. Hypoxia-inducible factor-1α (HIF-1α) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1α allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified. ⋯ These results indicate that HIF-1α in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure.
-
Am. J. Respir. Crit. Care Med. · Feb 2014
Evidence for Right Ventricular Lipotoxicity in Heritable Pulmonary Arterial Hypertension.
Shorter survival in heritable pulmonary arterial hypertension (HPAH), often due to BMPR2 mutation, has been described in association with impaired right ventricle (RV) compensation. HPAH animal models are insulin resistant, and cells with BMPR2 mutation have impaired fatty acid oxidation, but whether these findings affect the RV in HPAH is unknown. ⋯ These data demonstrate that Bmpr2 mutation affects RV stress responses in a transgenic rodent model. Impaired RV hypertrophy and triglyceride and ceramide deposition are present as a function of RV mutant Bmpr2 in mice; fatty acid oxidation impairment in human HPAH RVs may underlie this finding. Further study of how BMPR2 mediates RV lipotoxicity is warranted.
-
Am. J. Respir. Crit. Care Med. · Feb 2014
Simultaneous Targeting of Interleukin-1 and -18 is Required for Protection against Inflammatory and Septic Shock.
Sepsis is one of the leading causes of death around the world. The failure of clinical trials to treat sepsis demonstrates that the molecular mechanisms are multiple and are still insufficiently understood. ⋯ Our data point toward the therapeutic potential of neutralizing IL-1 and IL-18 simultaneously in sepsis, rather than inhibiting the upstream inflammatory caspases.
-
Am. J. Respir. Crit. Care Med. · Feb 2014
Models for Intensive Care Training: A European Perspective.
The diversity of European culture is reflected in its healthcare training programs. In intensive care medicine (ICM), the differences in national training programs were so marked that it was unlikely that they could produce specialists of equivalent skills. The Competency-Based Training in Intensive Care Medicine in Europe (CoBaTrICE) program was established in 2003 as a Europe-based worldwide collaboration of national training organizations to create core competencies for ICM using consensus methodologies to establish common ground. ⋯ There are still wide variations in structures and processes of training in ICM across Europe, although there has been agreement on a set of common program standards. The combination of a common "product specification" for an intensivist, combined with persisting variation in the educational context in which competencies are delivered, provides a rich source of research inquiry. Pedagogic research in ICM could usefully focus on the interplay between educational interventions, healthcare systems and delivery, and patient outcomes, such as including whether competency-based program are associated with lower error rates, whether communication skills training is associated with greater patient and family satisfaction, how multisource feedback might best be used to improve reflective learning and teamworking, or whether increasing the proportion of specialists trained in acute care in the hospital at weekends results in better patient outcomes.