Matthew G. Drake

Toll-like Receptor 7 Rapidly Relaxes Human Airways

RATIONALE Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. OBJECTIVES To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. METHODS Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. MEASUREMENTS AND MAIN RESULTS The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. CONCLUSIONS TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.

The Therapeutic Potential of Toll-like Receptor 7 Stimulation in Asthma

Asthma is an inflammatory disorder of the airways frequently characterized by an excessive Th2 adaptive immune response. Activation of Toll-like receptor (TLR)-7, a single-stranded viral RNA receptor that is highly expressed in the airways, triggers a rapid innate immune response and favors a subsequent Th1 response. Because of this role in pulmonary immunoregulation, TLR7 has gained considerable interest as a therapeutic target in asthma. Synthetic TLR7 ligands, including the imidazoquinolines imiquimod (R837) and resiquimod (R848), and 8-hydroxyadenine derivatives have been developed for other clinical indications. TLR7 activation prevents ovalbumin-induced airway hyperreactivity, eosinophilic inflammation, goblet cell hyperplasia and airway remodeling in murine models of asthma. TLR7 activation also inhibits viral replication in the lung and prevents virus-induced airway hyperreactivity. Furthermore, it has recently been shown that stimulating TLR7 rapidly relaxes airway smooth muscle, dilating the airways. This bronchodilating effect, which occurs in seconds to minutes and depends on rapid production of nitric oxide, indicates that TLR7 can signal via previously unrecognized pathways. The effects of decreasing the allergic Th2 response, acting as an immediate bronchodilator, and promoting an antiviral immune environment, make TLR7 an attractive drug target. We examine the current understanding of TLR7 as a therapeutic target and its translation to asthma treatment in humans.

Spontaneous Pneumothoraces in Patients with Birt–Hogg–Dubé Syndrome

Rationale: Spontaneous pneumothorax is a common complication of Birt‐Hogg‐Dubé syndrome (BHD). Objectives: The optimal approach to treatment and prevention of BHD‐associated spontaneous pneumothorax, and to advising patients with BHD regarding risk of pneumothorax associated with air travel, is not well established. Methods: Patients with BHD were recruited from the Rare Lung Diseases Clinic Network and the BHD Foundation and surveyed about disease manifestations and air travel experiences. Results: A total of 104 patients completed the survey. The average age at diagnosis was 47 years, with an average delay from first symptoms of 13 years. Pulmonary cysts were the most frequent phenotypic manifestation of BHD, present in 85% of patients. Spontaneous pneumothorax was the presenting manifestation that led to the diagnosis of BHD in 65% of patients, typically after the second episode (mean, 2.4 episodes). Seventy‐nine (76%) of 104 patients had at least one spontaneous pneumothorax during their lifetime, and 82% had multiple pneumothoraces. Among patients with multiple pneumothoraces, 73% had an ipsilateral recurrence, and 48% had a subsequent contralateral spontaneous pneumothorax following a sentinel event. The mean ages at first and second pneumothoraces were 36.5 years (range, 14‐63 yr) and 37 years (range, 20‐55 yr), respectively. The average number of spontaneous pneumothoraces experienced by patients with a sentinel pneumothorax was 3.6. Pleurodesis was generally performed after the second (mean, 2.4) ipsilateral pneumothorax and reduced the ipsilateral recurrence rate by half. A total of 11 episodes of spontaneous pneumothorax occurred among eight patients either during or within the 24‐hour period following air travel, consistent with an air travel‐related pneumothorax rate of 8% per patient and 0.12% per flight. Prior pleurodesis reduced the occurrence of a subsequent flight‐related pneumothorax. Conclusions: Spontaneous pneumothorax is an important, recurrent manifestation of pulmonary involvement in patients with BHD, and pleurodesis should be considered following the initial pneumothorax to reduce the risk of recurrent episodes. In general, in patients with BHD, pneumothorax occurs in about 1‐2 per 1,000 flights, and the risk is lower among patients with a history of prior pleurodesis.

Toll-like receptor-2/6 and Toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs.

Respiratory virus infections cause airway hyperreactivity (AHR). Preventative strategies for virus-induced AHR remain limited. Toll-like receptors (TLRs) have been suggested as a therapeutic target because of their central role in triggering antiviral immune responses. Previous studies showed that concurrent treatment with TLR2/6 and TLR9 agonists reduced lethality and the microbial burden in murine models of bacterial and viral pneumonia. This study investigated the effects of TLR2/6 and TLR9 agonist pretreatment on parainfluenza virus pneumonia and virus-induced AHR in guinea pigs in vivo. Synthetic TLR2/6 lipopeptide agonist Pam₂CSK₄ and Class C oligodeoxynucleotide TLR9 agonist ODN2395, administered in combination 24 hours before virus infection, significantly reduced viral replication in the lung. Despite a fivefold reduction in viral titers, concurrent TLR2/6 and TLR9 agonist pretreatment did not prevent virus-induced AHR or virus-induced inhibitory M2 muscarinic receptor dysfunction. Interestingly, the TLR agonists independently caused non-M2-dependent AHR. These data confirm the therapeutic antiviral potential of TLR agonists, while suggesting that virus inhibition may be insufficient to prevent virus-induced airway pathophysiology. Furthermore, TLR agonists independently cause AHR, albeit through a distinctly different mechanism from that of parainfluenza virus.

Eosinophil and airway nerve interactions in asthma

Airway eosinophils are increased in asthma and are especially abundant around airway nerves. Nerves control bronchoconstiction and in asthma, airway hyperreactivity (where airways contract excessively to inhaled stimuli) develops when eosinophils alter both parasympathetic and sensory nerve function. Eosinophils release major basic protein, which is an antagonist of inhibitory M2 muscarinic receptors on parasympathetic nerves. Loss of M2 receptor inhibition potentiates parasympathetic nerve‐mediated bronchoconstriction. Eosinophils also increase sensory nerve responsiveness by lowering neurons’ activation threshold, stimulating nerve growth, and altering neuropeptide expression. Since sensory nerves activate parasympathetic nerves via a central neuronal reflex, eosinophils’ effects on both sensory and parasympathetic nerves potentiate bronchoconstriction. This review explores recent insights into mechanisms and effects of eosinophil and airway nerve interactions in asthma.

Ozone‐induced eosinophil recruitment to airways is altered by antigen sensitization and tumor necrosis factor‐α blockade

Ozone is an atmospheric pollutant that causes lung inflammation and airway hyperresponsiveness. Ozones effects occur in two distinct phases that are mediated by different populations of eosinophils. In the acute phase 1 day after exposure, mature airway‐resident eosinophils alter parasympathetic nerve function that results in airway hyperresponsiveness. At this time point, the severity of hyperresponsiveness correlates with the number of eosinophils in close proximity to airway nerves, but not with eosinophils in bronchoalveolar lavage. Three days later, newly divided eosinophils are recruited to airways by a tumor necrosis factor‐α‐dependent mechanism. These new eosinophils paradoxically attenuate ozone‐induced airway hyperresponsiveness. Ozones effects on airway tissue eosinophils and nerve‐associated eosinophils 3 days after exposure are unknown. Thus, we tested ozones effects on eosinophils in airway subepithelium and around airway nerves 1 and 3 days after ozone in nonsensitized and ovalbumin‐sensitized guinea pigs with or without the tumor necrosis factor‐α antagonist, etanercept, and compared changes in eosinophils with ozone‐induced airway hyperresponsiveness. More eosinophils were present in small, noncartilaginous airways and along small airway nerves compared to large cartilaginous airways in all treatment groups. The number of airway and nerve‐associated eosinophils were unaffected 1 day after ozone exposure, whereas significantly fewer airway eosinophils were present 3 days later. Airway and nerve‐associated eosinophils were also decreased in small airways 3 days after ozone in sensitized animals. These changes were blocked by etanercept. Airway eosinophils, but not nerve‐associated or bronchoalveolar lavage eosinophils correlated with airway hyperresponsiveness 3 days after ozone. Our findings indicate ozone causes persistent alterations in airway eosinophils and reinforce the importance of characterizing eosinophils’ effects within distinct airway compartments.

Toll-Like Receptor 7-Targeted Therapy in Respiratory Disease

Allergic asthma and allergic rhinitis are inflammatory diseases of the respiratory tract characterized by an excessive type-2 T helper cell (Th2) immune response. Toll-like receptor 7 (TLR7) is a single-stranded viral RNA receptor expressed in the airway that initiates a Th1 immune response and has garnered interest as a novel therapeutic target for treatment of allergic airway diseases. In animal models, synthetic TLR7 agonists reduce airway hyperreactivity, eosinophilic inflammation, and airway remodeling while decreasing Th2-associated cytokines. Furthermore, activation of TLR7 rapidly relaxes airway smooth muscle via production of nitric oxide. Thus, TLR7 has dual bronchodilator and anti-inflammatory effects. Two TLR7 ligands with promising pharmacologic profiles have entered clinical trials for the treatment of allergic rhinitis. Moreover, TLR7 agonists are potential antiviral therapies against respiratory viruses. TLR7 agonists enhance influenza vaccine efficacy and also reduce viral titers when given during an active airway infection. In this review, we examine the current data supporting TLR7 as a therapeutic target in allergic airway diseases.

High-Flow Nasal Cannula Oxygen in Adults: An Evidence-based Assessment

High-flow nasal cannula oxygenation has distinct advantages over other oxygen devices because of its unique effects on respiratory physiology. In particular, adjustable oxygen delivery and flow-dependent carbon dioxide clearance reduce work of breathing and better match inspiratory demand during respiratory distress. Historically, few studies had evaluated whether the physiologic effects of these devices translated into clinical benefit. However, recent publications have begun to address this knowledge gap. High-flow nasal cannula oxygenation has been shown to have similar, and in some cases superior clinical efficacy compared with conventional low-flow oxygen supplementation and noninvasive positive pressure ventilation in acute hypoxemic respiratory failure. High-flow nasal cannula oxygenation also prevents reintubations in medical and postoperative surgical populations, provides preoxygenation for laryngoscopy, and supports oxygenation during bronchoscopy. This review examines the evidence for high-flow nasal cannula oxygenation use in adults, including a focus on the unique effects of high flow on respiratory physiology and keys for tailoring flow for specific clinical scenarios.

Smoking Marijuana and the lungs

www.thoracic.org C LI P A N D C O P Y The harmful effects of tobacco smoke are well known, but we have less information about the health effects of marijuana. Few research studies have been done since marijuana remains illegal in most countries, and since marijuana can be inhaled in many ways (e.g. water pipes, joints, vaping etc). It is likely that in frequent users (and some less frequent users), marijuana harms the lungs, and that there is not a safe way to smoke marijuana.

TLR7 agonist-induced bronchodilation: key mechanistic questions remain

to the editor: The role of Toll-like receptor-7s (TLR7) in innate immunity against single-stranded RNA viruses is well established. Recently, our group found TLR7 agonists also relax guinea pig and human airway smooth muscle strips via production of nitric oxide ([1][1], [2][2]). Immunostaining