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Viral infections are the most common cause of upper respiratory infections; they frequently infect adults once or twice and children 6 to 8 times annually. In most cases, these infections are self-limiting and resolve. However, many patients with chronic rhinosinusitis (CRS) relay that their initiating event began with an upper respiratory infection that progressed in both symptom severity and duration. Viruses bind to sinonasal epithelia through specific receptors, thereby entering cells and replicating within them. Viral infections stimulate interferon-mediated innate immune responses. Recent studies suggest that viral infections may also induce type 2 immune responses and stimulate the aberrant production of cytokines that can result in loss of barrier function, which is a hallmark in CRS. The main purpose of this review will be to highlight common viruses and their associated binding receptors and highlight pathophysiologic mechanisms associated with alterations in mucociliary clearance, epithelial barrier function, and dysfunctional immune responses that might lead to a further understanding of the pathogenesis of CRS., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown., Research Question: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids?, Study Design and Methods: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12)., Results: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts., Interpretation: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Mucociliary clearance through coordinated ciliary beating is a major innate defense removing pathogens from the lower airways, but the pathogen sensing and downstream signaling mechanisms remain unclear. We identified virulence-associated formylated bacterial peptides that potently stimulated ciliary-driven transport in the mouse trachea. This innate response was independent of formyl peptide and taste receptors but depended on key taste transduction genes. Tracheal cholinergic chemosensory cells expressed these genes, and genetic ablation of these cells abrogated peptide-driven stimulation of mucociliary clearance. Trpm5-deficient mice were more susceptible to infection with a natural pathogen, and formylated bacterial peptides were detected in patients with chronic obstructive pulmonary disease. Optogenetics and peptide stimulation revealed that ciliary beating was driven by paracrine cholinergic signaling from chemosensory to ciliated cells operating through muscarinic M3 receptors independently of nerves. We provide a cellular and molecular framework that defines how tracheal chemosensory cells integrate chemosensation with innate defense., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The antifibrinolytic agent, tranexamic acid (TXA), an inhibitor of plasmin formation, currently is evaluated to reduce bleeding in various conditions, including traumatic brain injury (TBI). Because plasmin is implicated in inflammation and immunity, we investigated the effects of plasmin inhibition on the immune response after TBI in the presence or absence of induced pneumonia. Wild-type mice treated with vehicle or TXA or mice deficient in plasminogen (plg -/- ) underwent TBI using the controlled cortical impact model. Mice were then subjected to Staphylococcus aureus induced pneumonia and the degree of immune competence determined. Significant baseline changes in the innate immune cell profile were seen in plg -/- mice with increases in spleen weight and white blood cell counts, and elevation in plasma interleukin-6 levels. The plg -/- mice subjected to TBI displayed no additional changes in these parameters at the 72 h or one week time point post-TBI. The plg -/- mice subjected to TBI did not exhibit any further increase in susceptibility to endogenous infection. Pneumonia was induced by intratracheal instillation of S. aureus. The TBI did not worsen pneumonia symptoms or delay recovery in plg -/- mice. Similarly, in wild type mice, treatment with TXA did not impact on the ability of mice to counteract pneumonia after TBI. Administration of TXA after TBI and subsequent pneumonia, however, altered the number and surface marker expression of several myeloid and lymphoid cell populations, consistent with enhanced immune activation at the 72 h time point. This investigation confirms the immune-modulatory properties of TXA, thereby highlighting its effects unrelated to inhibition of fibrinolysis.

Background: Balanced composition of a well-functioning pulmonary surfactant is crucial and essential for normal breathing. Here, we explored whether the composition of lipids recovered by broncho-alveolar lavage (BAL) in children with cystic fibrosis (CF) differ from children with protracted bacterial bronchitis (PBB) and controls. We wanted to differentiate, if alterations are primarily caused by the disease process or secondary due to an increased amount of cell-membrane lipids derived from inflammatory cells., Methods: Comprehensive lipidomics profiles of BAL fluid from children diagnosed with CF, PBB and controls were generated by electrospray ionization tandem mass spectrometry analysis. BAL cell differential and numbers were examined., Results: 55 children (37 patients with CF, 8 children with PBB and 10 controls) were included in this study. Results showed comparable total quantities of lipids in all groups. Phospholipids were the major lipid fraction and similar in all groups, whereas the fractions of cholesteryl esters were less and of free cholesterol were increased in children with CF. Among the phospholipids, patients with CF had higher proportion of the non-surfactant membrane-lipids in the classes phosphatidylethanolamine based plasmalogens (PE P), phosphatidylethanolmine (PE) and phosphatidylserine (PS), but a lower proportion of phosphatidylcholine (PC) compared to healthy controls. No such changes were identified in the BAL fluid of children diagnosed with PBB. No differences were observed for the surfactant lipids dipalmitoyl-phosphatidylcholin (PC 32:0) and phosphatidylglycerol (PG)., Conclusions: In CF patients with neutrophilic airway inflammation the lipid composition for surfactant phospholipid components were unchanged, whereas alteration in lipid profile were characteristic for those found in membranes of inflammatory cells. We suspect that the changes in CF were caused by the prolonged inflammation in contrast to a relatively short standing process in PBB., (Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The primary purpose of pulmonary ventilation is to supply oxygen (O 2 ) for sustained aerobic respiration in multicellular organisms. However, a plethora of abiotic insults and airborne pathogens present in the environment are occasionally introduced into the airspaces during inhalation, which could be detrimental to the structural integrity and functioning of the respiratory system. Multiple layers of host defense act in concert to eliminate unwanted constituents from the airspaces. In particular, the mucociliary escalator provides an effective mechanism for the continuous removal of inhaled insults including pathogens. Defects in the functioning of the mucociliary escalator compromise the mucociliary clearance (MCC) of inhaled pathogens, which favors microbial lung infection. Defective MCC is often associated with airway mucoobstruction, increased occurrence of respiratory infections, and progressive decrease in lung function in mucoobstructive lung diseases including cystic fibrosis (CF). In this disease, a mutation in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene results in dehydration of the airway surface liquid (ASL) layer. Several mice models of Cftr mutation have been developed; however, none of these models recapitulate human CF-like mucoobstructive lung disease. As an alternative, the Scnn1b transgenic ( Scnn1b -Tg+) mouse model overexpressing a transgene encoding sodium channel nonvoltage-gated 1 , beta subunit ( Scnn1b ) in airway club cells is available. The Scnn1b -Tg+ mouse model exhibits airway surface liquid (ASL) dehydration, impaired MCC, increased mucus production, and early spontaneous pulmonary bacterial infections. High morbidity and mortality among mucoobstructive disease patients, high economic and health burden, and lack of scientific understanding of the progression of mucoobstruction warrants in-depth investigation of the cause of mucoobstruction in mucoobstructive disease models. In this review, we will summarize published literature on the Scnn1b -Tg+ mouse and analyze various unanswered questions on the initiation and progression of mucobstruction and bacterial infections., Competing Interests: The authors declare that they have no competing interests.

Bronchiectasis is a chronic respiratory disorder characterized by persistent productive cough and recurrent chest infections secondary to permanent structural airway damage. The current treatment strategies for this debilitating disorder are limited to prompt antibiotic treatment of infective exacerbations and regular airway clearance techniques. Despite its high morbidity and associated mortality across all age groups, it has been a neglected area of research in respiratory medicine and there remain no licensed disease-modifying therapies. In this review, we have explored the numerous potential therapeutic targets to break the vicious cycle of infection and inflammation seen in these patients and the novel therapeutic agents that have been developed to target them. We have reviewed the role of novel anti-inflammatory agents designed to target the persistent neutrophilic inflammatory infiltrate seen in bronchiectatic airways, including neutrophil elastase inhibitors, CXCR2 (CXC chemokine receptor 2) antagonists, DPP-1 (dipeptidyl peptidase 1) inhibitors, PDE4 (phosphodiesterase 4) inhibitors and statins. Furthermore, we have explored novel targets to improve mucociliary clearance, namely ENaC (epithelial sodium channel) inhibitors, and discussed the potential of alternative antimicrobial strategies such as inhaled phages. Our review highlights the importance of a multi-faceted approach to bronchiectasis management, which aims not only to eradicate or suppress bronchial infection but also to break the cycle of persistent airway inflammation that results in progressive lung damage in these patients., (© 2018 Asian Pacific Society of Respirology.)

Objective: To determine whether induced sputum (IS) with hypertonic saline inhalation is safe to use in asthmatics within 24 hours of two commonly used airway challenges, namely endotoxin and dust mite allergen, and to assess whether IS can enhance mucociliary clearance (MCC) rates in asthmatics., Methods: IS (three 7-minute inhalation periods of 3%, 4%, and 5% hypertonic saline) was employed before (N = 29) and within 24 hours of inhaled challenges with endotoxin (N = 13) and dust mite allergen (N = 12) in a cohort of mild to moderate asthmatics. Safety was assessed by lung function (Forced Expiratory Volume in 1 second; FEV1) and MCC was measured using a radiolabeled gamma scintigraphy method (Tcm99 sulfur colloid). IS was performed pre and post MCC., Results: No significant lung function decrement was observed before or after inhaled challenges with endotoxin or dust mite allergen. IS significantly enhanced MCC rates before and after inhaled endotoxin challenge., Conclusion: Based on a small cohort, IS is safe to use in mild to moderate asthmatics before and within 24 hours of inhaled challenges with endotoxin and dust mite allergen. Furthermore, IS has beneficial effects on host defense function in asthmatics by enhancing MCC rates.

In the healthy lung the opportunistic pathogen, Pseudomonas aeruginosa , is rapidly eliminated by mucociliary clearance, a process that is dependent on the activity of the CFTR anion channel that, in concert with a number of other transport proteins, regulates the volume and composition of the periciliary surface liquid. This fluid layer is essential to enable cilia to clear pathogens from the lungs. However, in cystic fibrosis (CF), mutations in the CFTR gene reduce Cl - and [Formula: see text] secretion, thereby decreasing periciliary surface liquid volume and mucociliary clearance of bacteria. In CF this leads to persistent infection with the opportunistic pathogen, P. aeruginosa , which is the cause of reduced lung function and death in ~95% of CF patients. Others and we have conducted studies to elucidate the effects of P. aeruginosa on wild-type and Phe508del-CFTR Cl - secretion as well as on the host immune response. These studies have demonstrated that Cif (CFTR inhibitory factor), a virulence factor secreted by P. aeruginosa , is associated with reduced lung function in CF and induces the ubiquitination and degradation of wt-CFTR as well as TAP1, which plays a key role in viral and bacterial antigen presentation. Cif also enhances the degradation of Phe508del-CFTR that has been rescued by ORKAMBI, a drug approved for CF patients homozygous for the Phe508del-CFTR mutation, thereby reducing drug efficacy. This review is based on the Hans Ussing Distinguished Lecture at the 2016 Experimental Biology Meeting given by the author., (Copyright © 2017 the American Physiological Society.)

Recurrent lung infections and pneumonia are emerging as significant comorbidities in the HIV-infected population in the era of combination antiretroviral therapy (cART). HIV infection has been reported to suppress nasal mucociliary clearance (MCC). Since the primary components driving nasal MCC and bronchial MCC are identical, it is possible that bronchial MCC is affected as well. Effective MCC requires optimal ciliary beating which depends on the maintenance of the airway surface liquid (ASL), a function of cystic fibrosis transmembrane conductance regulator (CFTR) activity and the integrity of the signaling mechanism that regulates ciliary beating and fluid secretion. Impairment of either component of the MCC apparatus can compromise its efficacy and promote microbial colonization. We demonstrate that primary bronchial epithelium expresses HIV receptor CD4 and co-receptors CCR5 and CXCR4 and can be infected by both R5 and X4 tropic strains of HIV. We show that HIV Tat suppresses CFTR biogenesis and function in primary bronchial epithelial cells by a pathway involving TGF-β signaling. HIV infection also interferes with bronchial epithelial cell differentiation and suppresses ciliogenesis. These findings suggest that HIV infection suppresses tracheobronchial mucociliary clearance and this may predispose HIV-infected patients to recurrent lung infections, pneumonia and chronic bronchitis., Competing Interests: The authors have declared that no competing interests exist.

The paper considers current approaches to mucoregulatory therapy for various inflammatory diseases of the respiratory system. It gives the advantages and disadvantages of common drugs used in their treatment. Emphasis is laid on the use of inhaled hypertonic saline of NaCl in combination with hyaluronic acid (Hyaneb). Clinical examples of its use in chronic obstructive pulmonary disease, acute and chronic bronchitis, and severe asthma are considered.

Cystic fibrosis (CF) lung disease is characterized by persistent and unresolved inflammation, with elevated proinflammatory and decreased anti-inflammatory cytokines, and greater numbers of immune cells. Hyperinflammation is recognized as a leading cause of lung tissue destruction in CF. Hyper-inflammation is not solely observed in the lungs of CF patients, since it may contribute to destruction of exocrine pancreas and, likely, to defects in gastrointestinal tract tissue integrity. Paradoxically, despite the robust inflammatory response, and elevated number of immune cells (such as neutrophils and macrophages), CF lungs fail to clear bacteria and are more susceptible to infections. Here, we have summarized the current understanding of immune dysregulation in CF, which may drive hyperinflammation and impaired host defense., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The airway epithelium is now considered to be central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as the first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. Herein, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, chronic obstructive pulmonary fibrosis and cystic fibrosis will be discussed., (Copyright ©ERS 2015.)

Cryptococcus neoformans is a medically important opportunistic fungal pathogen with a polysaccharide capsule surrounding the yeast-like cells. In hosts with impaired cell-mediated immunity such as AIDS, uncontrolled infection causes life-threatening meningoencephalitis. In immunocompetent individuals, the host immune response usually limits the growth of the fungal pathogen at the primary infected site, where it may persist, without completely eradicated, in a latent state because of its ability to escape from killing by macrophages. Th1 response in adaptive immunity is essential for the host defense to cryptococcal infection, in which interferon (IFN)-γ polarizes innate macrophages into fungicidal M1 macrophages. Recently, we found that caspase recruitment domain family member (CARD9), an adaptor protein in a signal transduction triggered by C-type lectin receptors, plays a key role in the early production of IFN-γ at the site of infection by recruiting NK cells and CD4(+) and CD8(+) memory-phenotype T cells. We also found that IL-4 produced by Th2 cells stimulates broncoepithelial cells to secrete mucin, which may lead to promotion in the mucociliary clearance of C. neoformans. Here, we summarize the up-to-date findings in the host defense mechanism to this infection with focusing on our recent data.

Acetylcholine (ACh) exerts various anti-inflammatory effects through α7 nicotinic ACh receptors (nAChRs). We have previously shown that secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of α7 nAChR signaling, is down-regulated both in an animal model of asthma and in human epithelial cells treated with an inflammatory cytokine related to asthma. Our aim of this study was to explore the effect of SLURP-1, signal through α7 nAChR, in the pathophysiology of airway inflammation. Cytokine production was examined using human epithelial cells. Ciliary beat frequency of murine trachea was measured using a high speed camera. The IL-6 and TNF-α production by human epithelial cells was augmented by siRNA of SLURP-1 and α7 nicotinic ACh receptor. The cytokine production was also dose-dependently suppressed by human recombinant SLURP-1 (rSLURP-1). The ciliary beat frequency and amplitude of murine epithelial cells were augmented by PNU282987, a selective α7 nAChR agonist. Those findings suggested that SLURP-1 and stimulus through α7 nicotinic ACh receptors actively controlled asthmatic condition by stimulating ciliary beating and also by suppressing airway inflammation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Mucociliary airway clearance is an innate defense mechanism that protects the lung from harmful effects of inhaled pathogens. In order to escape mechanical clearance, airway pathogens including Streptococcus pneumoniae (pneumococcus) are thought to inactivate mucociliary clearance by mechanisms such as slowing of ciliary beating and lytic damage of epithelial cells. Pore-forming toxins like pneumolysin, may be instrumental in these processes. In a murine in vitro airway infection model using tracheal epithelial cells grown in air-liquid interface cultures, we investigated the functional consequences on the ciliated respiratory epithelium when the first contact with pneumococci is established. High-speed video microscopy and live-cell imaging showed that the apical infection with both wildtype and pneumolysin-deficient pneumococci caused insufficient fluid flow along the epithelial surface and loss of efficient clearance, whereas ciliary beat frequency remained within the normal range. Three-dimensional confocal microscopy demonstrated that pneumococci caused specific morphologic aberrations of two key elements in the F-actin cytoskeleton: the junctional F-actin at the apical cortex of the lateral cell borders and the apical F-actin, localized within the planes of the apical cell sides at the ciliary bases. The lesions affected the columnar shape of the polarized respiratory epithelial cells. In addition, the planar architecture of the entire ciliated respiratory epithelium was irregularly distorted. Our observations indicate that the mechanical supports essential for both effective cilia strokes and stability of the epithelial barrier were weakened. We provide a new model, where--in pneumococcal infection--persistent ciliary beating generates turbulent fluid flow at non-planar distorted epithelial surface areas, which enables pneumococci to resist mechanical cilia-mediated clearance.

Vaccination and antimicrobial therapy remain the cornerstones of the management of pneumococcal pneumonia. Despite significant successes, the capacity of the pneumococcus to evolve in the face of the selective pressure of anticapsular immunity challenges immunization programs. Treatment focuses on antimicrobial therapy but ignores the central role of the dysregulated inflammatory response during pneumonia. Future therapeutic approaches need to build on the considerable recent advances in our understanding of the pathogenesis of pneumococcal pneumonia, including those from models of pneumonia. Enhancement of the essential components of the host response that prevents most colonized individuals from developing pneumonia and strategies to limit inappropriate inflammatory responses to lower respiratory tract infection are approaches that could be exploited to improve disease outcome. This review highlights recent discoveries relating to the microbial and host determinants of microbial clearance and regulation of the inflammatory response, which provide clues as to how this could be achieved in the future.

Purpose of Review: Primary ciliary dyskinesia (PCD) is a rare and heterogeneous disease that is often misdiagnosed or diagnosed late with more advanced sequelae. PCD primarily effects the respiratory tract, yet most research focuses on the lower respiratory tract manifestations, most of which is derived from research on cystic fibrosis. Little is known about the management of the upper respiratory tract sequelae of PCD. This review summarizes the available evidence for the management of otologic and sinonasal manifestations of PCD., Recent Findings: The natural history of otitis media with effusion and hearing loss in PCD appears to fluctuate into adulthood and does not resolve by the age of 9 years, regardless of treatment, as previously assumed. Ventilation tube insertion improves hearing in PCD, but may lead to a higher rate of otorrhoea when compared with the general population. Sinonasal disease in PCD is poorly studied; however, it appears that patients with chronic rhinosinusitis (CRS) may benefit from long-term macrolide therapy and endoscopic sinus surgery (ESS) in recalcitrant disease. Therapies targeted at improving mucociliary clearance have not been tested specifically in PCD. Pharmacogenetic therapy is currently under investigation to target the primary defect in PCD., Summary: Otologic sequeale in PCD should undergo lifelong evaluation and monitoring and ventilation tube insertion should be considered to avoid complications of chronic hearing loss. Sinonasal disease benefits from macrolide therapy and ESS. Randomized controlled trials of treatment efficacy of the upper respiratory tract manifestations of PCD are lacking.

Background/objective: Respiratory infections including atypical bacteria Mycoplasma pneumoniae (Mp) contribute to the pathobiology of asthma and chronic obstructive pulmonary disease (COPD). Mp infection mainly targets airway epithelium and activates various signaling pathways such as nuclear factor κB (NF-κB). We have shown that short palate, lung, and nasal epithelium clone 1 (SPLUNC1) serves as a novel host defense protein and is up-regulated upon Mp infection through NF-κB activation in cultured human and mouse primary airway epithelial cells. However, the in vivo role of airway epithelial NF-κB activation in host defense against Mp infection has not been investigated. In the current study, we investigated the effects of in vivo airway epithelial NF-κB activation on lung Mp clearance and its association with airway epithelial SPLUNC1 expression., Methodology/main Results: Non-antimicrobial tetracycline analog 9-t-butyl doxycycline (9-TB) was initially optimized in mouse primary tracheal epithelial cell culture, and then utilized to induce in vivo airway epithelial specific NF-κB activation in conditional NF-κB transgenic mice (CC10-(CA)IKKβ) with or without Mp infection. Lung Mp load and inflammation were evaluated, and airway epithelial SPLUNC1 protein was examined by immunohistochemistry. We found that 9-TB treatment in NF-κB transgene positive (Tg+), but not transgene negative (Tg-) mice significantly reduced lung Mp load. Moreover, 9-TB increased airway epithelial SPLUNC1 protein expression in NF-κB Tg+ mice., Conclusion: By using the non-antimicrobial 9-TB, our study demonstrates that in vivo airway epithelial NF-κB activation promotes lung bacterial clearance, which is accompanied by increased epithelial SPLUNC1 expression.

Background: Acute exacerbations in allergic asthmatics may lead to impaired ability to clear mucus from the airways, a key factor in asthma morbidity., Objective: The purpose of this study was to determine the effect of inhaled house dust mite challenge on the regional deposition of inhaled particles and mucociliary clearance (MCC) in allergic asthmatics., Methods: We used gamma scintigraphy (inhalation of (99m) Tc -sulphur colloid particles) to measure the regional particle deposition and MCC in allergic asthmatics (n=12) 4 h following an inhaled dust mite allergen challenge (Dermatophagoides farinae extract; PD(max) =fall in forced expiratory volume in 1 s of 10%) for comparison with baseline non-challenge measures., Results: In responders (n=9 PD(max) dose), lung function returned to pre-challenge values by 3 h but was significantly decreased at 6 and 24 h in three of the responders (i.e. late-phase response) and induced sputum eosinophils were increased at 24 h post-challenge (P<0.05). Responders showed enhanced bronchial airway deposition of inhaled particles (P<0.05) and slowed clearance from the central lung zone (P<0.01) at 4 h post-challenge compared with the baseline (no allergen challenge) that was predicted by the PD(max) allergen concentration (r=-0.70, P<0.05). The decline in lung function at 24 h post-challenge correlated with reduced MCC from the central lung zone (r=-0.78, P<0.02) and PD(max) . Non-responders (n=3) showed no change in lung function, regional deposition or MCC post-challenge vs. baseline., Conclusions and Clinical Relevance: These data suggest that regional deposition and clearance of inhaled particles may be sensitive for detecting mild airway obstruction associated with early- and late-phase allergen-induced effects on mucus secretions. The study was listed on clinicaltrials.gov (NCT00448851)., (© 2011 Blackwell Publishing Ltd.)

Secretory IgA (SIgA) antibodies represent the first line of antigen-specific immune defense protecting the mucosal surfaces against environmental pathogens and antigens, and maintaining homeostasis with the commensal microbiota. The polymeric immunoglobulin receptor (pIgR) has the dual role of transporting locally produced dimeric IgA across mucosal epithelia, and serving as the precursor of secretory component, a glycoprotein that enhances the immune functions of SIgA. The complex regulation of pIgR expression and transcytosis by host and microbial factors is finely tuned to optimize the role of SIgA in mucosal immunity. Disruption of this regulatory network in disease states similar to inflammatory bowel disease can result in profound consequences for mucosal homeostasis and systemic sequelae. Future research into the function and regulation of pIgR and SIgA may offer new insights into the prevention and treatment of infectious and inflammatory diseases that originate at mucosal surfaces.

Objective: To evaluate the effect of IgE-mediated hypersensitivity on mucociliary clearance time (MCCT) and clinical severity, as indicated by total nasal symptoms score (TNSS) and peak expiratory flow index (PEFI)., Design: A prospective cross-sectional study., Setting: Tertiary medical center., Participants: One hundred twenty-nine patients with rhinitis and 48 healthy control subjects., Main Outcome Measures: Results of an allergy skin prick test in the patients with rhinitis categorized them as allergic (AR) or nonallergic (non-AR). We evaluated TNSS and PEFI in the patient group and assessed MCCTs from the patients in the rhinitis groups and the healthy controls., Results: The AR group patients had the longest MCCT, followed by patients in the non-AR group and the healthy controls (mean MCCTs, 14.36, 10.87, and 6.55 minutes, respectively). The AR group patients had significantly higher TNSS and worse PEFI compared with patients in the non-AR group (P = .002 and P = .03, respectively). We found a significant positive correlation of MCCTs with TNSS, and MCCTs showed a tendency to be inversely correlated with PEFI (rho = 0.43 [P < .001] and r = -0.22 [P = .05], respectively). In AR group patients, the wheal responses to Dermatophagoides pteronyssinus, Dermatophagoides farinae, American cockroach, and Bermuda grass were fairly correlated with the MCCTs (r = 0.39 [P = .001], r = 0.40 [P = .001], r = 0.34 [P = .01], and r = 0.36 [P = .02], respectively). The maximal wheal response among various positive allergen responses was well correlated with the MCCTs (r = 0.54 [P < .001])., Conclusion: A prolonged MCCT, significant correlation between MCCTs and the magnitude of allergen reactivity, and clinical severity suggest an impact of IgE-mediated hypersensitivity on mucociliary clearance function.

IL-33 plays an important role in inflammatory diseases including hypersensitive diseases like asthma, autoimmune diseases like rheumatoid arthritis, cardiovascular diseases like heart failure and neurodegenerative diseases like Alzheimer's disease. Here we reported the generation of an IL-33 transgenic mouse, in which mouse IL-33 full-length cDNA was controlled under the CMV promoter. The transgenic IL-33 was released as a cleaved form with molecular weight of 18kDa in pulmonary, nephritic, cardiac and pancreatic tissues in transgenic mice and the pI of 18kDa peptide was about pH 3-5 on the 2D PAGE which was similar with the activated peptide of IL-33. Histological analysis showed massive airway inflammation with infiltration of eosinophils around bronchi and small blood vessels, hyperplasia of goblet cells and accumulation of mucus-like material in pulmonary tissue of transgenic mice. An increase of IL-5, IL-8, IL-13 and IgE was detected in bronchoalveolar lavage fluid (BALF) of transgenic mice, which are inflammatory factors. These findings suggest transgenic IL-33 could be cleaved and secreted in an activated form and play an important role in the pathogenesis of pulmonary inflammation.

Purpose of Review: This article reviews recent insights surrounding the etiology and pathogenesis of chronic rhinosinusitis. In particular, we highlight the increasing recognition of host-mediated mechanisms in driving mucosal inflammation., Recent Findings: Published differences between epithelium from patients with chronic rhinosinusitis and normal controls can be classified into several broad categories. Alterations are reported in the various components of the epithelial innate immune system including epithelial-expressed pattern-recognition receptors (PRRs) and the levels of antimicrobial innate immune effector molecules. Other studies demonstrate differences in the proteins involved in maintaining epithelial barrier integrity. Finally, recent studies show in chronic rhinosinusitis that epithelial-derived cytokines, chemokines and inducible surface proteins are involved in recruiting and activating cells of the adaptive immune system., Conclusion: The sinonasal epithelium provides a mechanical and innate immune barrier to a diverse array of environmental agents. This barrier also plays a key role in regulating the acquired mucosal immune response in the nose. Recent studies suggest that defects in this barrier may foster development of chronic sinonasal inflammation in response to environmental agents, and pathogenic or commensal organisms. The ability to dissect and analyze defects in the inflammatory response in rhinosinusitis may help identify novel targets for drug development.

Background: Defects in the fontanel region of the lateral nasal wall have been described in the literature as "accessory" or "secondary" ostia. The authors consider them a sign of chronic maxillary sinusitis. Along with mucus recirculation between the natural ostium and the fontanel defect, we call it the Two Holes Syndrome. The aim of this study was to determine the incidence of fontanel defects in patients with chronic rhinosinusitis (CRS) and in healthy subjects., Methods: Eighty-eight hundred seventy-nine outpatients with CRS were examined by means of nasal fiberendoscopy. The control group consisted of 1442 healthy volunteers with no previous history of CRS., Results: Defect in the posterior fontanel was found in 1713/8879 CRS patients (19.3%). It was bilateral in 1165 cases (68.03%). Defect in the anterior fontanel was found in 54 patients (0.61%). The circulating mucus ring was identified in 162 patients with fontanel defects (9.17%). The defect in the posterior fontanel was found in 7/1442 healthy volunteers (0.48%). It was never bilateral, the circulating mucus was not observed and defect in the anterior fontanel was not found., Conclusion: Posterior fontanel defects were found more frequently in CRS patients than in healthy subjects. These defects have been clinically related to chronic infection of the maxillary sinus and should not be called "accessory" or "secondary" ostia. CRS with defects of the fontanel region and mucus recirculation can promote a number of health disturbances (chronic postnasal drip, headache, and cough). We named this entity the Two Holes Syndrome.

Objective/hypothesis: The Allergic Rhinitis and Its Impact on Asthma (ARIA) classification of allergic rhinitis (AR) is based on the severity and duration of nasal symptoms. Whether the nasal symptoms actually represent underlying nasal inflammation is unclear. The aim of this study was to evaluate the correlation between nasal symptoms and nasal inflammation using mucociliary clearance time (MCCT) in AR., Study Design: A prospective cross-sectional study., Methods: 73 AR patients were classified according to ARIA class: mild or moderate-severe intermittent AR (MIAR or MSIAR) and mild or moderate-severe persistent AR (MPAR or MSPAR). Each nasal symptom was scored as 1 to 3 on a severity scale (mild-moderate-severe). The sum of the individual nasal symptom scores gave the total symptoms score (TSS). MCCT was determined with the charcoal-saccharin method. MCCTs between ARIA classes were compared and correlations between TSS or days with symptoms per week (DSW) and MCCT were analyzed., Results: Of the patients, 67.1% were moderate-severe degree. MSPAR had the worst MCCT, followed by MSIAR, MPAR, and MIAR (mean MCCTs of 14.32, 13.87, 11.94, and 10.28 minutes, respectively). TSS was well correlated with MCCT (P = .538, P < .001). DSW was also correlated with MCCT, but did not reach statistical significance (r = 0.217, P = .065). The mean MCCT of overall nasal symptoms increased along with each score step and a significant difference was noted between scores 2 and 3 (P < .001)., Conclusions: A high percentage of moderate-severe disease and a significant correlation of the severity and MCCTs suggest an important heterogeneity in this disease severity group. Discriminating between moderate and severe rhinitis should help to obtain homogeneous populations and develop improved disease management strategies.

Citrobacter rodentium, a natural mouse pathogen, belongs to the family of extracellular enteric pathogens that includes enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC). C. rodentium shares many virulence factors with EPEC and EHEC and relies on attaching-and-effacing lesion formation for colonization and infection of the gut. In vivo, C. rodentium infection is characterized by increased epithelial cell proliferation, mucosal thickening, and a TH1-type immune response, but with protective immunity believed to be mediated by serum immunoglobulin G (IgG). In this work, we characterize the immune response and pathology of mice lacking the p50 subunit of the transcription factor nuclear factor kappa B (NF-kappaB) during C. rodentium infection. We show that p50(-/-) mice are unable to clear C. rodentium infection. Furthermore, these animals show a reduced influx of immune cells into infected colonic tissue and greater levels of mucosal hyperplasia and the cytokines tumor necrosis factor alpha and gamma interferon. Surprisingly, despite being unable to eliminate infection, p50(-/-) mice showed markedly higher levels of anti-Citrobacter IgG and IgM, suggesting that antibody alone is not responsible for bacterial clearance. These data also demonstrate that non-NF-kappaB-dependent defenses are insufficient to control C. rodentium infection, and hence, the NF-kappaB p50 subunit is critical for defense against this noninvasive pathogen.

Purpose of Review: Mucociliary clearance is a critical host defense mechanism of the airways. Effective mucociliary clearance requires appropriate mucus production and coordinated ciliary activity. The important role of these two components is best demonstrated in disorders such as primary ciliary dyskinesia and cystic fibrosis, both of which lead to lifelong recurrent respiratory tract infections. We review the methods used to analyze mucociliary clearance., Recent Findings: Utilization of microdialysis probes has improved temporal resolution of mucociliary clearance in murine airways, availing many genetic mouse models to critical mucociliary clearance analysis, while improved fixation technique for transmission electron microscopy has allowed for detailed resolution of the airway surface liquid. High-speed digital video analysis has improved quantification of ciliary beat frequency while advancements in air-liquid interface culturing techniques have generated in-vitro models to investigate mucociliary clearance., Summary: Advancements in techniques for analysis of mucociliary clearance have improved our understanding of the interaction between the respiratory epithelium and the airway surface liquid, resulting in the ability to study pathologic processes involving mucociliary clearance in great detail.

Mycoplasma pneumoniae protein P200 was localized to the terminal organelle, which functions in cytadherence and gliding motility. The loss of P200 had no impact on binding to erythrocytes and A549 cells but resulted in impaired gliding motility and colonization of differentiated bronchial epithelium. Thus, gliding may be necessary to overcome mucociliary clearance.

Lysozyme is a ubiquitous and abundant, cationic, antimicrobial polypeptide of leukocytes and epithelia, but its biological function in host defense is largely unexplored. To ascertain the role of lysozyme during bacterial infection of murine airways, we exposed the airways of lysozyme M-deficient (lys M-/-) mice to the pulmonary pathogen Pseudomonas aeruginosa and examined the host's response to infection. Despite partial compensation as a result of the appearance of lysozyme P in the infected airways of lys M-/- mice, these lys M-/- mice showed decreased clearance of P. aeruginosa compared with their lys M+/- or lys M+/+ littermates. Lysozyme contributes to optimal clearance of P. aeruginosa from the murine airways.

The object of this study was to investigate the impact of cigarette smoke on bacterial clearance and immune inflammatory parameters after infection with Pseudomonas aeruginosa in mice. We observed a delayed rate of bacterial clearance in smoke-exposed compared with sham-exposed mice. This was associated with increased inflammation characterized by greater numbers of neutrophils and mononuclear cells in the bronchoalveolar lavage. After infection, we observed increased levels of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6) and chemokines (monocyte chemoattractant protein-1 [MCP-1] and macrophage inflammatory protein-2 [MIP-2]) as well as myeloperoxidase and proteolytic activity in the lungs of smoke-exposed compared with sham-exposed animals. Delayed clearance was associated with increased morbidity and greater weight loss of smoke-exposed mice. After delivery of inactivated bacteria, we observed a similar inflammatory response, clinical score, and tumor necrosis factor-alpha expression in smoke- and sham-exposed animals, suggesting that increased inflammation and altered clinical presentation are due to the delayed rate of bacterial clearance. Our findings suggest that cigarette smoke affects respiratory immune-inflammatory responses elicited by bacteria. We postulate that altered respiratory host defense may be implicated in smoking-related diseases such as chronic obstructive pulmonary disease.

Objective: This review focuses on the role of cysteinyl leukotrienes (cysLTs) in nasal allergy. The purpose was to provide knowledge of the role of cysLTs in the pathophysiology of nasal allergy and the role of antileukotrienes in the treatment of nasal allergies. Materials and methods We conducted a literature review., Results: The proinflammatory effects of cysLTs have been well described in asthma. Antileukotrienes have proved to be an effective anti-inflammatory treatment for asthma patients. Similar to pathogenesis of asthma, cysLTs exert potent inflammatory effects in the upper airways and play a role in the pathogenesis of allergic rhinitis and other nasal allergies., Conclusion: Antileukotriene treatment appears to be beneficial in nasal allergies. Allergic rhinitis is a complex, IgE-mediated inflammatory disease of the upper airways. It is the most common allergic disease, occurring in 10% to 30% of adults and up to 30% of children. It may be perennial or seasonal. Sneezing, itching, watery rhinorrhea, and nasal obstruction are classic symptoms. It may impair cognition, school/work performance and productivity, behavior, mood, and quality of life. On physical examination, clear secretions, nasal congestion, pink-bluish nasal mucosa, the allergic salute, and allergic shiners may be detected. Allergic rhinitis is a common comorbid condition with asthma, sinusitis, otitis media, nasal polyposis, and respiratory infections.

Macrolides are used primarily as antibiotics, but they may have other effects. This was first suggested after clinical experience showed that macrolides have an important therapeutic role some inflammatory airway diseases in which infection is not considered as an important etiologic factor. In vitro, ex vivo and in vivo experiments revealed that macrolides reinforce local defense mechanisms in the upper respiratory tract such as mucociliary clearance and epithelial impermeability. In addition, macrolides influence acute inflammation, by altering concentrations of cytokines and changing leucocyte functions. This paper aims to review the current knowledge on the non-antibiotic effects of macrolides on local defense mechanisms and acute inflammation in the upper respiratory tract.

The aim of this study was to test the effects of the iodine bromide water of the thermal baths of Salsomaggiore on patients suffering from specific nonseasonal rhinitis (Dermatophagoides Farinae and Dermatophagoides Pteronyssinus). The patients, 80 in all, were divided in two groups (group A and group B). All of the patients underwent rhinoscopic examination, anterior rhinomanometry, prick test, rast screening, total IgE assay together with that of the other immunoglobulins (IgA, IgM, IgG), mucociliary clearance evaluation and were asked to evaluate their degree of nasal obstruction, before and after 30 days of treatment. Group A carried out the experiment by applying endonasal Acqua Sal spray seven times a day for 30 days; group B used oily drops for the same time and with the same frequency. At the end of the trial period, the patients in group A showed a 100% improvement in their subjective perception of their symptomatology, in comparison with a 33% improvement in the control group. A characteristic decrease in the IgE and increase in the IgA was observed in the serum of the patients who had been treated with Acqua Sal spray. Iodine bromide water has a general and local anti-inflammatory effect, which is also due to the activation of the corticosurrenal system (with a relative increase in cortisol). The cleansing action of hypertonic water in the nasal cavities must also be cited, as it minimizes contact between the mucosa and allergens.

1. AN IMPORTANT RELATIONSHIP: There is a strong relationship between tubular dysfunction, tympanic depression and effusion of the tympanic cavity. 2. TWO IMPORTANT PHENOMENA: Increased secretory capacity of the mucosa and decreased mucociliary clearance subsequent to a reduction in the number of ciliated cells have an important impact. 3. CONTINUUM: Rhinopharyngeal infection, acute middle ear infection and seromucosal otitis constitutes a continuum demonstrated by the fact that PCR (polymerase chain reaction) studies reveal the same germs in the rhinopharynx, in the middle ear fluid, and in seromucous otitis (SMO) effusions. 4., Bacteria and Viruses: By producing toxin, bacteria and viruses induce severe inflammatory reactions in SMO, triggering the cascaded of inflammation mediators. 5. MEDIATORS: Several elements participating in the cascade of inflammatory events have been demonstrated in human patients and animal models of SMO despite the minimal number of elements producing inflammation mediators initially. Recurrent favoring factors have a primordial effect. 6., Allergy: The clinical and epidemiologic data are widely debated, but do not favor the hypothesis of an allergic reaction, yet several studies have demonstrated that mediators of the allergic response are present in SMO effusions. 7. ANTIBIOTICS: Used in short-term regimens, antibiotics have a favorable [not readable: see text] on SMO, but their duration of action is short due to the persistent inflammatory reactions. 8. ORAL CORTICOSTEROIDS: The beneficial effect of oral corticosteroids in SMO is generally short-lived with a rapid decline in efficacy after a few weeks. 9. LONG DURATION AND RELAPSE: SMO is usually a long-standing highly recurrent condition proscribing use of long-term systemic corticosteroids. It might be interesting to assess the contribution of local corticosteroid therapy after classical "acute" treatment associating antibiotics and a short course of oral corticosteroids. 10. OTHER OPTIONS: Clinical trials using other treatment options in SMO have not been conclusive for mucolytic, decongestant or antihistamine agents.

Pulmonary host defenses comprise a redundant system of protective mechanisms against invasion of the lungs by pathogenic microbes. The upper and lower airways are uniquely suited to contain and remove organisms that gain access to the respiratory mucosa. If the balance between host and organism is disputed, however, microbial clearance may be ineffective, and infection established. Pulmonary host defense mechanisms, which provide the basis for several current therapeutic strategies, are reviewed.

BALB/c mice were orally immunized with liposomes containing outer membrane proteins (OMPs) isolated from nontypeable Haemophilus influenzae (NTHi) and GM-53 as an adjuvant daily for 14 days. Anti-OMP IgA antibody titers in nasal wash, saliva, and fecal extract were significantly increased after the immunization. Although anti-OMP IgM and IgG antibodies were detected in serum, serum IgA antibodies specific to OMPs were not found. Enzyme-linked immunospot assay showed an increased number of OMP-specific IgA-secreting cells in nasal passages, intestinal lamina propria lymphocytes, and the spleen. Following oral immunization, a suspension of live NTHi was injected into the nose; nasal washes were collected 12 h after the inoculation. The number of NTHi in nasal washes was significantly reduced in mice immunized with liposomes containing OMPs and GM-53 compared to that in mice immunized with liposomes containing GM-53 alone. There was a significant negative correlation between the number of NTHi and anti-OMP IgA antibody titers in nasal washes. These findings suggest that antigen-specific IgA responses in the nose can be induced by oral immunization with OMPs and might be associated with the ability to clear NTHi from the nose.

Tumor necrosis factor-alpha (TNF-alpha) has been shown to stimulate the resistance of alveolar macrophages and neutrophils to Legionella pneumophila in vitro. To determine whether endogenous TNF-alpha is necessary for host defense against legionellosis in vivo, anti-TNF-alpha IgG or control IgG was administered to rats exposed to aerosolized L. pneumophila. Treatment with anti-TNF-alpha neutralized >90% of the intrapulmonary TNF-alpha response to infection, resulting in persistent pneumonitis and failure to clear L. pneumophila from the lungs. Depletion of TNF-alpha limited the recruitment of mononuclear cells to the lungs and resulted in a progressive increase in the proportion of alveolar macrophages that were infected; neutrophil recruitment and phagocytosis were not impaired. Both systemic and intrapulmonary IFN-gamma levels were significantly higher in rats depleted of TNF-alpha. These observations indicate that TNF-alpha is required for the prompt resolution of pneumonic legionellosis and point to a direct role for TNF-alpha in the activation of phagocytes.

Although studies indicate that alveolar macrophages participate in host defense against Pneumocystis carinii, their role in organism degradation and clearance from the lung has not yet been established. We, therefore, quantified the uptake and degradation of 35S-labeled P. carinii by cultured macrophages, demonstrating significant degradation of P. carinii over 6 h. We further evaluated the role of macrophages in elimination of P. carinii from the living host. Rats received either intratracheal PBS, liposomal PBS (L-PBS), or liposomal dichloromethylene diphosphonate (L-Cl2MDP), a preparation which leads to selective depletion of macrophages. Over 72 h, L-Cl2MDP-treated animals had loss of > 85% of their alveolar macrophages. In contrast, L-PBS-treated rats had cellular differentials identical to rats receiving PBS. Macrophage-depleted rats and controls were next inoculated with P. carinii and organism clearance was determined after 24 h. P. carinii elimination was evaluated with both cyst counts and an ELISA directed against glycoprotein A (gpA), the major antigen of P. carinii. Both assays indicated that macrophage-depleted rats had substantial inpairment of P. carinii clearance compared to L-PBS- or PBS-treated rats. These data provide the first direct evidence that macrophages mediate elimination of P. carinii from the living host.

The airways and gas-exchanging surfaces of the lung are an important interface between the host and the external environment. Potentially injurious particulates and gases continuously impact on this extensive epithelial surface. The pulmonary defense apparatus, which uses anatomic barriers, aerodynamics, soluble factors and a multitude of cellular processes, protects the airways and the alveolar surfaces so that gas exchange between the host and the environment can occur.