Pulmonary pharmacology & therapeutics
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Pulm Pharmacol Ther · Aug 2011
The Sphingosine-1 Phosphate receptor agonist FTY720 dose dependently affected endothelial integrity in vitro and aggravated ventilator-induced lung injury in mice.
Lung barrier protection by Sphingosine-1 Phosphate (S1P) has been demonstrated experimentally, but recent evidence suggests barrier disruptive properties of high systemic S1P concentrations. The S1P analog FTY720 recently gained an FDA approval for treatment of multiple sclerosis. In case of FTY720 treated patients experiencing multiple organ dysfunction syndrome the drug may accumulate due to liver failure, and the patients may receive ventilator therapy. ⋯ Low FTY720 concentrations (0.1 mg/kg) reduced lung permeability in mechanically ventilated mice, but 2 mg/kg FTY720 increased pulmonary vascular permeability in ventilated mice accompanied by endothelial apoptosis, while not affecting permeability in non-ventilated mice. Moreover, hyperoxic mechanical ventilation sensitized the pulmonary vasculature to a barrier disrupting effect of FTY720, resulting in worsening of ventilator induced lung injury. In conclusion, the current data suggest FTY720 induced endothelial barrier dysfunction, which was probably caused by proapoptotic effects and enhanced by mechanical ventilation.
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In the early 1990's ion channels of the Transient Receptor Potential (TRP) class were implicated in the afferent sensory loop of the cough reflex and in the heightened cough sensitivity seen in disease. Agonists of the TRPV1 capsaicin receptor such as vanilloids and protons were demonstrated to be amongst the most potent chemical stimuli which cause cough. However, more recently, the TRPA1 receptor (not activated by capsaicin) has become of interest in the cough field because it is known to be activated by ligands such as acrolein which is present in air pollution and the acrid smoke from organic material. ⋯ Activation of these vagal sensory afferents leads to central reflexes including dyspnoea, changes in breathing pattern and cough. Recently, it has been demonstrated that stimulating TRPA1 channels activates vagal bronchopulmonary C-fibres in the guinea pig and rodent lung, and recent data have shown that TRPA1 ligands cause cough in both animal models and normal volunteers. In summary, due to their activation by a wide range of irritant and chemical substances, either by exogenous agents, endogenously produced mediators during inflammation or by oxidant stress, we suggest TRPA1 channels should be considered as one of the most promising targets currently identified for the development of novel anti-tussive drugs.
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Pulm Pharmacol Ther · Jun 2011
Cough in the elderly: a novel strategy for preventing aspiration pneumonia.
Management of cough in the elderly with a deteriorated physical and mental status has received little focus. Since an aged population is rapidly increasing in developed countries, the research in this population are warranted. Cough reflex sensitivity in the elderly was shown to be hypersensitive, normosensitive and hyposensitive. ⋯ In the treatment of aspiration pneumonia, one of the most challenging steps is the start of eating for patients who usually fast at the time of hospitalization. By combining the methods to restore the cough reflex sensitivity and swallowing reflex, we developed a protocol to start eating in the elderly patients with aspiration pneumonia. Using the protocol, we reduced the incidence of re-aspiration due to start of eating in patients with aspiration pneumonia to one third of the patients without the protocol.
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Pulm Pharmacol Ther · Jun 2011
ReviewFunctional implications of the multiple afferent pathways regulating cough.
At least 2 airway vagal afferent nerve subtypes can directly initiate coughing upon activation. The capsaicin-insensitive, acid-sensitive mechanoreceptors innervating the larynx, trachea and large bronchi regulate coughing in both conscious and anesthetized animals. ⋯ The basic properties of the afferent nerves regulating cough, their interactions both centrally and peripherally and their responsiveness to tussive stimuli are briefly reviewed. Also reviewed is evidence against the notion of 2 completely separate types of cough regulated by parallel afferent pathways, asserting instead that multiple afferent nerve subtypes contribute to all types of cough.
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Within the group of Idiopathic Interstitial Pneumonias (IIPs), above all Idiopathic Pulmonary Fibrosis (IPF) poses a considerable diagnostic and therapeutic problem. Although genetic profiling indicates that IPF, Non Specific Interstitial Pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP) are distinctly different diseases, in every day practice these diseases can be difficult to tell apart. Furthermore, treatment of these diseases is notoriously difficult. ⋯ Several biomarkers, such as KL-6, surfactant proteins and circulating fibrocytes, appear to contribute to our insight into disease progression and prognosis. It is however uncertain whether these markers give us additional information to common diagnostic tests and their value has as yet to be validated for every day practice. Fortunately, the potential of biomarkers is increasingly recognized and biomarker data are prospectively gathered in current placebo-controlled therapeutic trials.