Linking structure and function in the vertebrate respiratory system: A tribute to August Krogh.

High rates of pulmonary gas exchange require three things: 1) that gases at the contact surface of the lung's capillaries are replenished rapidly from the environment; 2) that this surface is large and thin; 3) that the capillaries are effectively perfused with blood. In spite of this uniform requirement, lungs have evolved complex and highly diverse architectures, but we have a poor understanding of the drivers of this diversity. Here, I briefly discuss some of the diversity in gross anatomical features directing airflow in avian and non-avian reptiles. I also review new insights into the cellular anatomy of the blood-gas barrier, which in mammals is composed of specialized endothelial as well as epithelial cells.

Utility of cone-beam CT imaging for the determination of feeding vessels during arterial embolization for massive hemoptysis.

PURPOSE: We aimed to evaluate the role of cone-beam computed tomography (CT) performed as an adjunct to angiography for the determination of feeding vessels responsible for bleeding during arterial embolization for massive hemoptysis. METHODS: In this retrospective study, 23 patients with massive hemoptysis who underwent cone-beam CT evaluation prior to arterial embolization from December 2014 to December 2017 were included. During the angiographic session, two interventional radiologists selected the possible feeding vessels that were likely to supply the bleeding target lesions. Contrast-enhanced cone-beam CT was performed at the indefinite feeding arteries as an adjunct to angiography to determine whether the artery was a real feeding vessel, based on whether the target lesion was detected in the perfused territory of the study artery on images. RESULTS: Selective cone-beam CT was successfully performed in 21 patients, at 26 possible feeding vessels that were detected by selective angiography. Cone-beam CT determined the feeding vessel in 24 arteries (92.3%) in 19 patients (90.5%). As a result of cone-beam CT findings, 16 of 24 study arteries were judged as definitively not feeding vessels (66.7%) and the remaining 8 study arteries were judged as definitively feeding vessels (33.3%). In 2 of 26 study arteries cone-beam CT could not determine the feeding vessel (7.7%). CONCLUSION: Cone-beam CT performed as an adjunctive technique to angiography is sufficient to provide adequate information for confident determination of the feeding vessel, which is essential for the operators to perform accurate embolization during arterial embolization for massive hemoptysis.

Airway and Pulmonary ß2-Adrenergic Vasodilatory Function in Current Smokers and Never Smokers.

BACKGROUND: Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of ß2-adrenoceptor-mediated vasodilation in smokers and never smokers. METHODS: In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 µg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived. RESULTS: Albuterol induced a substantial drop in mean (± SE) PVR (-67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% ± 3% vs -3.1% ± 6%; P < .02). CONCLUSIONS: These results are consistent with a dysfunction in a ß2-adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium.

Comparison of Dexmedetomidine and Remifentanil on Airway Reflex and Hemodynamic Changes during Recovery after Craniotomy.

PURPOSE: During emergence from anesthesia for a craniotomy, maintenance of hemodynamic stability and prompt evaluation of neurological status is mandatory. The aim of this prospective, randomized, double-blind study was to compare the effects of dexmedetomidine and remifentanil on airway reflex and hemodynamic change in patients undergoing craniotomy. MATERIALS AND METHODS: Seventy-four patients undergoing clipping of unruptured cerebral aneurysm were recruited. In the dexmedetomidine group, patients were administered dexmedetomidine (0.5 µg/kg) for 5 minutes, while the patients of the remifentanil group were administered remifentanil with an effect site concentration of 1.5 ng/mL until endotracheal extubation. The incidence and severity of cough and hemodynamic variables were measured during the recovery period. Hemodynamic variables, respiration rate, and sedation scale were measured after extubation and in the post-anesthetic care unit (PACU). RESULTS: The incidence of grade 2 and 3 cough at the point of extubation was 62.5% in the dexmedetomidine group and 53.1% in the remifentanil group (p=0.39). Mean arterial pressure (p=0.01) at admission to the PACU and heart rate (p=0.04 and 0.01, respectively) at admission and at 10 minutes in the PACU were significantly lower in the dexmedetomidine group. Respiration rate was significantly lower in the remifentanil group at 2 minutes (p<0.01) and 5 minutes (p<0.01) after extubation. CONCLUSION: We concluded that a single bolus of dexmedetomidine (0.5 µg/kg) and remifentanil infusion have equal effectiveness in attenuating coughing and hemodynamic changes in patients undergoing cerebral aneurysm clipping; however, dexmedetomidine leads to better preservation of respiration.

Endoscopic transmucosal direct puncture sclerotherapy for management of airway vascular malformations.

OBJECTIVES/HYPOTHESIS: To describe a multidisciplinary approach to the treatment of airway vascular malformations (venous or lymphatic) with direct suspension rigid laryngoscopy and direct puncture transmucosal bleomycin sclerotherapy injected under road-mapping fluoroscopic monitoring, supplemented by Dyna-computed tomography utilization. STUDY DESIGN: Case series. METHODS: We performed a retrospective medical record and imaging review of four patients with venous malformations or lymphatic malformations located in the airway. Patients were treated with a combination of direct suspension laryngoscopy or rigid nasopharyngoscopy and image-guided direct puncture bleomycin sclerotherapy. RESULTS: Two patients presented to our institution with extensive lymphatic malformation of the neck, parapharyngeal, and retropharyngeal spaces, and two presented with venous malformation of the nasopharynx and oropharynx. All patients were treated with multiple sclerotherapy and debulking procedures before undergoing combined direct transmucosal puncture bleomycin sclerotherapy guided by direct laryngoscopy or nasopharyngoscopy. All patients had complete resolution of disease while maintaining a safe airway. CONCLUSIONS: A multidisciplinary approach to airway vascular malformations with a combination of endoscopy and direct puncture bleomycin sclerotherapy was demonstrated to be a safe and effective treatment in our patient cohort. Direct laryngoscopy and nasopharyngoscopy provide easy access to the nasopharynx, oropharynx, retro- and/or parapharyngeal spaces and larynx. Unlike traditional agents, bleomycin induces minimal edema and therefore is an ideal substance to treat airway lesions.

Effects of ONO-6950, a novel dual cysteinyl leukotriene 1 and 2 receptors antagonist, in a guinea pig model of asthma.

We assessed in this study the anti-asthmatic effects of ONO-6950, a novel cysteinyl leukotriene 1 (CysLT1) and 2 (CysLT2) receptors dual antagonist, in normal and S-hexyl glutathione (S-hexyl GSH)-treated guinea pigs, and compared these effects to those of montelukast, a CysLT1 selective receptor antagonist. Treatment with S-hexyl GSH reduced animals LTC4 metabolism, allowing practical evaluation of CysLT2 receptor-mediated airway response. ONO-6950 antagonized intracellular calcium signaling via human and guinea pig CysLT1 and CysLT2 receptors with IC50 values of 1.7 and 25 nM, respectively (human receptors) and 6.3 and 8.2 nM, respectively (guinea pig receptors). In normal guinea pigs, both ONO-6950 (1 or 0.3 mg/kg, p.o.) and the CysLT1 receptor antagonist montelukast (0.3 or 0.1 mg/kg, p.o.) fully attenuated CysLT1-mediated bronchoconstriction and airway vascular hyperpermeability induced by LTD4. On the other hand, in S-hexyl GSH-treated guinea pigs ONO-6950 at 3 mg/kg, p.o. or more almost completely inhibited bronchoconstriction and airway vascular hyperpermeability elicited by LTC4, while montelukast showed only partial or negligible inhibition of these airway responses. In ovalbumin sensitized guinea pigs, treatment with S-hexyl GSH on top of pyrilamine and indomethacin rendered antigen-induced bronchoconstriction sensitive to both CysLT1 and CysLT2 receptor antagonists. ONO-6950 strongly inhibited this asthmatic response to the level attained by combination therapy with montelukast and BayCysLT2RA, a selective CysLT2 receptor antagonist. These results clearly demonstrate that ONO-6950 is an orally active dual CysLT1/LT2 receptor antagonist that may provide a novel therapeutic option for patients with asthma.

Cerebrovascular reactivity in young subjects with sleep apnea.

STUDY OBJECTIVES: Regional brain alterations may be involved in the pathogenesis and adverse consequences of obstructive sleep apnea (OSA). The objectives for the current study were to (1) determine cerebrovascular reactivity in the motor areas that control upper airway musculature in patients with OSA, and (2) determine whether young patients with OSA have decreased cerebrovascular reactivity in response to breath holding. DESIGN: Case-control study. SETTING: Academic center. PARTICIPANTS: Twelve subjects with OSA (age 24-42 y; apnea-hypopnea index 17; interquartile range [IQR] 9, 69 per hour) and control subjects (n = 10; age 29-44 y; AHI 2; IQR 1, 3 per hour). MEASUREMENTS AND RESULTS: Subjects underwent blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) while awake, swallowing, and breath holding. In subjects with OSA, during swallowing, there was less activity in the brainstem than in controls (P = 0.03) that remained reduced after adjusting for cortical motor strip activity (P = 0.036). In OSA subjects, brain regions of increased cerebrovascular reactivity (38; IQR 17, 96 cm(3)) was smaller than that in controls (199; IQR 5, 423 cm(3); P = 0.01). In OSA subjects, brain regions of decreased cerebrovascular reactivity during breath hold was greater (P = 0.01), and the ratio of increased-to-decreased brain regions was lower than that of controls (P = 0.006). Adjustment for cerebral volumes, body mass index, and white matter lesions did not change these results substantively. CONCLUSIONS: In patients with obstructive sleep apnea (OSA), diminished change in brainstem activity during swallowing and reduced cerebrovascular reactivity may contribute to the etiopathogenesis and adverse cerebrovascular consequences, respectively. We speculate that decreased cerebral auto-regulation may be causative of gray matter loss in OSA.

Lower respiratory tract hemorrhage associated with 2009 pandemic influenza A (H1N1) virus infection.

BACKGROUND: Influenza-associated lower respiratory tract hemorrhage (LRTH) has been reported in previous pandemics and is a rare complication of seasonal influenza virus infection. We describe patients with LRTH associated with 2009 pandemic influenza A (H1N1) (pH1N1) virus infection identified from April 2009 to April 2010 in the United States. METHODS: We ascertained patients with pH1N1-associated LRTH through state and local surveillance, the Emerging Infections Program, and CDCs Infectious Diseases Pathology Branch. All patients had influenza A, evidence of pneumonia, and evidence of LRTH. RESULTS: We identified 44 cases; the median number of days from illness onset to clinical signs of LRTH was one. Hemoptysis or respiratory tract bleeding was documented in 40% of pH1N1-associated LRTH cases, often present early during the course of illness. Twenty-one (48%) patients with LRTH had no other hemorrhagic diatheses. Seven (23%) patients with LRTH received antiviral treatment within two days of illness onset. CONCLUSIONS: During influenza season, clinicians should consider influenza infection in the differential diagnosis for patients presenting with hemoptysis or other signs or symptoms of LRTH. While the impact of timing of antiviral therapy on this complication has not been studied, the rapid progression of LRTH may support use of early empiric therapy. Continued investigation is necessary to betterdefine the clinical spectrum of both seasonal influenza- and pH1N1-associated LRTH.

Tityus serrulatus venom increases vascular permeability in selected airway tissues in a mast cell-independent way.

Tityus serrulatus venom (Tsv)-induced pulmonary edema can occur in severe envenomation and the mechanisms involved are not completely understood. Therefore, we studied the effect of pharmacological modulation of the mast cell activation and the histamine antagonism on airways edema (investigated by Evans blue dye extravasation) and measured 5-hydroxytryptamine (5-HT) concentration in bronchoalveolar lavage fluid (BALF) in rats envenomed by Tsv. Additionally, the in vitro effect of Tsv on mast cells was studied using histological method and 5-HT release from mesenteric and peritoneal mast cells. We found that i.v. injection of Tsv increase vascular permeability in trachea, upper and lower bronchi and in lung parenchyma. This was not affected by ketotifen, a mast cell "stabilizer," or by pretreatment with pyrilamine (histamine H1 receptor antagonist). Moreover, 5-HT was not found in BALF of envenomed rats. In vitro experiments showed that Tsv did not induce mast cell degranulation nor release of 5-HT by mesenteric or peritoneal mast cells, in sharp contrast to preparations challenged by a mast cell activator, compound 48/80. In conclusion, our results show that Tsv causes strong edema in rat airways which is independent of mast cell activation and show that mast cells are not directly activated by Tsv.

Multiple organ failure syndrome in the newborn: morphological and immunohistochemical data.

Multiple organ failure (MOF) syndrome, also known as multiple organ dysfunction syndrome (MODS) represents a common but complex problem in critically ill patients in neonatal intensive care unit (NICU) centers, and a major cause of morbidity and mortality in newborns. MOF is considered the result of an inappropriate generalized inflammatory response of the newborn to a variety of acute insults. This study was aimed at analyzing, at histology, multiple organ pathological changes in two newborns admitted to the NICU center of our University Hospital, who showed a progressive clinical picture of MOF, in order to verify the pathological changes of vascular structures and of endothelial cells in the different organs affected by MOF. All the samples obtained at autopsy for histological examination showed specific organ pathological changes, especially related to modifications in vascular structures and, in particular, in endothelial cells. The most interesting findings were found in the intestinal barrier, in the lower respiratory tract and in the endothelial barrier. The loss of the gut barrier could allow the passage into the blood of microbial factors that could trigger the production of tumor necrosis factor α (TNFα) leading to endothelial damage. Our preliminary study underlines the principal role probably played by intestinal and vascular changes in the origin of MOF in newborns.

WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial pneumonia causing a loss of respiratory surface area due to a proliferative fibrotic response involving hyperplastic, hypertrophic, and metaplastic epithelium, cystic honeycomb change, septal expansion, and variable inflammation. Wnt (wingless) signaling glycoproteins are known to be involved in lung development and tissue repair, and are up-regulated in patients with IPF. Based on previous qRT-PCR data showing increased Wnt7B in lungs of IPF patients, a systematic, quantitative examination of its tissue site distribution was undertaken. METHODS: Tissue samples from the Lung Tissue Research Consortium (LTRC) of 39 patients diagnosed with mild to severe IPF/usual interstitial pneumonia (UIP) and 19 normal patients were examined for the immunolocalization of Wnt7B. RESULTS: In normal lung, moderate Wnt7B reactivity was confined to airway epithelium, smooth muscle of airways and vasculature, and macrophages. IPF lung showed strong Wnt7B reactivity in fibroblastic foci, dysplastic airway and alveolar epithelium, and in highly discrete subepithelial, basement membrane-associated regions. All reactive sites were sized and counted relative to specific microscopic regions. Those in the subepithelial sites were found in significantly greater numbers and larger relative area compared with the others. No reactive sites were present in normal patient controls. CONCLUSIONS: The results demonstrate Wnt7B to be expressed at high concentrations in regions of active hyperplasia, metaplasia, and fibrotic change in IPF patients. In this context and its previously established biologic activities, Wnt7B would be expected to be of potential importance in the pathogenesis of IPF.

Autonomic neural control of intrathoracic airways.

Autonomic neural control of the intrathoracic airways aids in optimizing air flow and gas exchange. In addition, and perhaps more importantly, the autonomic nervous system contributes to host defense of the respiratory tract. These functions are accomplished by tightly regulating airway caliber, blood flow, and secretions. Although both the sympathetic and parasympathetic branches of the autonomic nervous system innervate the airways, it is the later that dominates, especially with respect to control of airway smooth muscle and secretions. Parasympathetic tone in the airways is regulated by reflex activity often initiated by activation of airway stretch receptors and polymodal nociceptors. This review discusses the preganglionic, ganglionic, and postganglionic mechanisms of airway autonomic innervation. Additionally, it provides a brief overview of how dysregulation of the airway autonomic nervous system may contribute to respiratory diseases.

Dynamics of airway blood vessels and lymphatics: lessons from development and inflammation.

Blood vessels and lymphatic vessels in the respiratory tract play key roles in inflammation. By undergoing adaptive remodeling and growth, blood vessels undergo changes that enable the extravasation of plasma and leukocytes into inflamed tissues, and lymphatic vessels adjust to the increased fluid clearance and cell traffic involved in immune responses. Blood vessels and lymphatics in adult airways are strikingly different from those of late-stage embryos. Before birth, blood vessels in mouse airways make up a primitive plexus similar to that of the yolk sac. This plexus undergoes rapid and extensive remodeling at birth. In the early neonatal period, parts of the plexus regress. Capillaries then rapidly regrow, and with arterioles and venules form the characteristic adult vascular pattern. Lymphatic vessels of the airways also undergo rapid changes around birth, when lymphatic endothelial cells develop button-like intercellular junctions specialized for efficient fluid uptake. Among the mechanisms that underlie the onset of rapid vascular remodeling at birth, changes in tissue oxygen tension and mechanical forces associated with breathing are likely to be involved, along with growth factors that promote the growth and maturation of blood vessels and lymphatics. Whatever the mechanisms, the dynamic nature of airway blood vessels and lymphatics during perinatal development foretells the extraordinary vascular plasticity found in many diseases.

Claudin-1 expression in airway smooth muscle exacerbates airway remodeling in asthmatic subjects.

BACKGROUND: Increased airway smooth muscle (ASM) mass is an essential component of airway remodeling and asthma development, and there is no medication specifically against it. Tight junction (TJ) proteins, which are expressed in endothelial and epithelial cells and affect tissue integrity, might exist in other types of cells and display additional functions in the asthmatic lung. OBJECTIVE: The aim of this study was to investigate the existence, regulation, and function of TJ proteins in ASM in asthmatic patients. METHODS: The expression and function of TJ proteins in primary ASM cell lines, human bronchial biopsy specimens, and a murine model of asthma were analyzed by means of RT-PCR, multispectral imaging flow cytometry, immunohistochemistry, Western blotting, 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester staining, tritiated thymidine incorporation, wound-healing assay, and luminometric bead array. RESULTS: Increased claudin-1 expression was observed in ASM of asthmatic patients, as well as in a murine model of asthma-like airway inflammation. Whereas IL-1ß and TNF-α upregulated claudin-1 expression, it was downregulated by the T(H)2 cytokines IL-4 and IL-13 in primary human ASM cells. Claudin-1 was localized to the nucleus and cytoplasm but not to the cell surface in ASM cells. Claudin-1 played a central role in ASM cell proliferation, as demonstrated by increased ASM cell proliferation seen with overexpression and decreased proliferation seen with small interfering RNA knockdown of claudin-1. Overexpression of claudin-1 induced vascular endothelial growth factor and downregulated IL-6, IL-8, and IFN-γ-induced protein 10 production by ASM cells. Claudin-1 upregulation by IL-1ß or TNF-α was suppressed by dexamethasone but not by rapamycin, FK506, or salbutamol. CONCLUSION: These results demonstrate that claudin-1 might play a role in airway remodeling in asthmatic patients by means of regulation of ASM cell proliferation, angiogenesis, and inflammation.

Gross and fine anatomy of the respiratory vasculature of the mudskipper, Periophthalmodon schlosseri (Gobiidae: Oxudercinae).

To illustrate vascular modification accompanying transition from aquatic to amphibious life in gobies, we investigated the respiratory vasculatures of the gills and the bucco-opercular cavities in one of the most terrestrially-adapted mudskippers, Periophthalmodon schlosseri, using the corrosion casting technique. The vascular system of Pn. schlosseri retains the typical fish configuration with a serial connection of the gills and the systemic circuits, suggesting a lack of separation of O(2)-poor systemic venous blood and O(2)-rich effluent blood from the air-breathing surfaces. The gills appear to play a limited role in gas exchange, as evidenced from the sparsely-spaced short filaments and the modification of secondary lamellar vasculature into five to eight parallel channels that are larger than red blood cell size, unlike the extensive sinusoidal system seen in purely water-breathing fishes. In contrast, the epithelia of the bucco-opercular chamber, branchial arches, and leading edge of the filaments are extensively laden with capillaries having a short (<10 µm) diffusion distance, which strongly demonstrate the principal respiratory function of these surfaces. These capillaries form spiral coils of three to five turns as they approach the epithelial surface. The respiratory capillaries of the bucco-opercular chamber are supplied by efferent blood from the gills and drained by the systemic venous pathway. We also compared the degree of capillarization in the bucco-opercular epithelia of Pn. schlosseri with that of the three related intertidal-burrowing gobies (aquatic, non-air-breathing Acanthogobius hasta; aquatic, facultative air-breathing Odontamblyopus lacepedii; amphibious air-breathing Periophthalmus modestus) through histological analysis. The comparison revealed a clear trend of wider distribution of denser capillary networks in these epithelia with increasing reliance on air breathing, consistent with the highest aerial respiratory capacity of Pn. schlosseri among the four species.

How airway venous malformations differ from airway infantile hemangiomas.

OBJECTIVE: To compare airway infantile hemangiomas (IHs) and venous malformations (VMs) clinically, radiographically, endoscopically, and histologically. DESIGN: Retrospective cohort study. SETTING: Tertiary care pediatric hospital. PATIENTS: The study included patients seen in the Vascular Anomaly Clinic, Seattle Children's Hospital, Seattle, Washington, between 2001 and 2008. METHODS: All patients with airway vascular anomalies were identified by searching the Vascular Anomaly Quality Improvement Database and hospital discharge data. The data, which were analyzed with descriptive statistics and the Fisher exact test, included presenting age, sex, presenting signs, lesion site, and radiographic, endoscopic, and histologic findings.. RESULTS: Seventeen patients with airway lesions were identified, 6 with VMs and 11 with IHs. Patients with VMs presented at a mean (SD) age of 11.3 (13.7) months (age range, 3-39 months), while those with IHs presented at 3 (1.8) months of age (age range, 1-6 months) (P = .03). The patients with IHs were predominantly female (9 of 11 [81%]), while no sex difference was noted among the patients with VMs (3 of 6 [50%]). All patients with IHs presented with stridor and cutaneous lesions, whereas patients with VMs more often presented with hemoptysis or dysphagia (P = .001). Computed tomographic angiograms demonstrated enhancing endolaryngeal lesions in all IHs, while VMs enhanced poorly. Endoscopically, IHs were transglottic, while VMs were postcricoid or epiglottic (P < .001). Histologically, immunostained lesions showed submucosal lobules of capillaries lined by GLUT-1 (glucose transporter isoform 1)-positive endothelium in IHs, whereas VMs consisted of loosely organized venous channels that lacked GLUT-1 staining. CONCLUSION: Patients with airway IHs and VMs differ in presenting age and signs, sex, airway lesion location, enhancement on computed tomographic angiograms, and histologic appearance.