American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Oct 2014
ReviewNew Therapeutic Targets in Idiopathic Pulmonary Fibrosis: Aiming to Rein in Runaway Wound Healing Responses.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U. S. Food and Drug Administration. ⋯ The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF.
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Am. J. Respir. Crit. Care Med. · Oct 2014
Comparative Study Clinical TrialNovel Tests for Diagnosis of Invasive Aspergillosis in Patients with Underlying Respiratory Diseases.
Invasive pulmonary aspergillosis has been increasingly reported in nonneutropenic patients, including those with underlying respiratory diseases. ⋯ Probable or proven invasive pulmonary aspergillosis was diagnosed in 14% of our study population and associated with significantly higher 30-day mortality rates. Although the performance of β-D-glucan was limited by low specificity and that of mycological culture by low sensitivity, the Aspergillus lateral-flow device seems to be a promising alternative to galactomannan testing, which remains the diagnostic gold standard for aspergillosis. Clinical trial registered with www.clinicaltrials.gov (NCT 02058316).
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Am. J. Respir. Crit. Care Med. · Oct 2014
Lipoxin Generation is Related to Soluble Epoxide Hydrolase Activity in Severe Asthma.
Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established. ⋯ LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).
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Am. J. Respir. Crit. Care Med. · Oct 2014
Observational StudyAsymptomatic HIV-infected Individuals on Antiretroviral Therapy Exhibit Impaired Lung CD4(+) T Cell Responses to Mycobacteria.
HIV-infected persons on antiretroviral therapy (ART) remain at higher risk of pulmonary tuberculosis (TB) than HIV-uninfected individuals. This increased susceptibility may be caused by impairment of alveolar macrophage (AM) function and/or mycobacteria-specific alveolar CD4(+) T-cell responses observed in HIV-infected ART-naive adults. ⋯ AM and mycobacteria-specific alveolar CD4(+) T-cell responses in HIV-infected adults on ART for less than 4 years are impaired and may partly explain the high risk of TB in HIV-infected individuals on ART. Strategies to augment ART to improve lung immune cell function and reduce the high incidence of TB in HIV-infected adults who initiate ART should be investigated.
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Am. J. Respir. Crit. Care Med. · Oct 2014
Randomized Controlled TrialSmooth Muscle in the Maintenance of Increased Airway Resistance Elicited by Methacholine in Humans.
Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs). ⋯ The maintenance of airway narrowing despite MCh clearance in humans is attributed to an intrinsic ability of ASM to maintain shortening during a progressive decrease of contractile stimulation.