Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease.

Airway diseases, including cigarette smoke-induced chronic bronchitis, cystic fibrosis, and primary ciliary dyskinesia are associated with decreased mucociliary clearance (MCC). However, it is not known whether a simple reduction in MCC or concentration-dependent mucus adhesion to airway surfaces dominates disease pathogenesis or whether decreasing the concentration of secreted mucins may be therapeutic. To address these questions, Scnn1b-Tg mice, which exhibit airway mucus dehydration/adhesion, were compared and crossed with Muc5b- and Muc5ac-deficient mice. Absence of Muc5b caused a 90% reduction in MCC, whereas Scnn1b-Tg mice exhibited an ∼50% reduction. However, the degree of MCC reduction did not correlate with bronchitic airway pathology, which was observed only in Scnn1b-Tg mice. Ablation of Muc5b significantly reduced the extent of mucus plugging in Scnn1b-Tg mice. However, complete absence of Muc5b in Scnn1b-Tg mice was associated with increased airway inflammation, suggesting that Muc5b is required to maintain immune homeostasis. Loss of Muc5ac had few phenotypic consequences in Scnn1b-Tg mice. These data suggest that: (i) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airway pathology; (ii) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (iii) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.

Primary ciliary dyskinesia and humoral immunodeficiency--is there a missing link?

BACKGROUND: Primary ciliary dyskinesia (PCD) and humoral mmunodeficiency (HID) are both rare disorders which cause recurrent upper and lower respiratory tract infections. OBJECTIVE: To examine the concurrence of PCD and HID in a patient cohort with known PCD. METHODS: Retrospective review of the patient files. RESULTS: We describe 11 patients of a cohort of 168 patients with PCD (6.5%) with a combination of PCD and some form of HID. The patients all presented with typical clinical symptoms for PCD, however the role of the concomitant immunological abnormalities is not clear. CONCLUSION: PCD and HID coincided in 6.5% of the patients. We suggest that a common pathophysiological pathway results in both disorders.

Managing upper respiratory tract complications of primary ciliary dyskinesia in children.

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.

Innate immune functions of the airway epithelium.

The epithelium of the respiratory tract forms a large surface area that maintains intimate contact with the environment. Through the act of breathing, this mucosal surface encounters an array of pathogens and toxic particulates. In response to these challenges many strategies have evolved to protect the host. These include the barrier functions of the epithelium, cough, mucociliary clearance, resident professional phagocytes, and the secretion of a number of proteins and peptides with host defense functions. Thus, the surface and submucosal gland epithelium of the conducting airways is a constitutive primary participant in innate immunity. In addition, this tissue may serve the function of a secondary amplifier of innate immune responses following neurohumoral input, stimulation with cytokines from cells such as alveolar macrophages, or engagement of pattern recognition receptors. Here, we provide an overview of the airway epithelium's role in pulmonary innate immunity, especially in the context of bacterial and viral infections, emphasizing findings from human cells and selected animal models. We also provide examples of human disease states caused by impaired epithelial defenses in the lung.

[The Kartagener syndrome]. / Das Kartagenersyndrom.

A 25-year-old woman with Kartagener's syndrome was admitted to hospital for laparoscopy because of sterility. Kartagener's syndrome is a rare disorder involving the combination of situs inversus, bronchiectasis and sinusitis. A dynein deficiency leads to ciliary dyskinesia. When general anaesthesia is to be induced in a patient with Kartagener's syndrome the following points must be borne in mind: ascertainment of the preoperative pulmonary status, antibiotic coverage, recognition of dextrocardia, necessity for aseptic techniques because of the possibility of abnormal neutrophil chemotaxis. Anticholinergic and antitussive medications are relatively contraindicated, as are nasal tubes. In the present case an intubation anaesthesia with thiopental, nitrous oxide, enflurane and succinylcholine was carried out; cefoxitin was administered for antibiotic treatment, and the patient made an uneventful recovery.

Association of rheumatoid arthritis with Kartagener's syndrome in a patient with HLA-DR1-DR4-B27 haplotype.

A case of severe seropositive rheumatoid arthritis associated with Kartagener's syndrome in a patient positive for B27, DR4, and DR1 has been presented. A number of immunological disturbances were observed, especially defective granulocyte function and depressed delayed hypersensitivity.

Polymorphonuclear neutrophil function in Kartagener's syndrome--report of two cases.

The clinical triad of Kartagener's syndrome (KS) includes situs inversus, sinusitis and bronchiectasis or at least chronic bronchitis. Immotile cilia with various ultrastructural defects have been seen in KS. Because the enhanced susceptibility to infections seen in KS it had been suspected due to significant abnormality of neutrophil function in addition to a defect of ciliary function. In this report, neutrophil functions such as PMN phagocytosis, PMN chemotaxis, Migration inhibition test and PMN bacterial killing test were studied in two cases of KS at a time when they were free of infection. The defects observed by us were only slight. We conclude that although neutrophil motility of patients is normal, the bactericidal activity is depressed in the early stage. Whether this abnormality enhances patient susceptibility to bacterial infections is not yet clear. The significance and actural mechanism for his delayed killing are now under investigation.

Immotile cilia syndrome: reduced chemotaxis and reduced number of intramembranous particles in granulocytes.

The neutrophil granulocytes of four patients with immotile cilia syndrome were investigated by means of freeze-fracture technique. Whereas most granulocytic functions (adherence, phagocytosis, killing of micro-organisms, reduction of NBT, and chemoluminescence) were in the normal range, chemotaxis of the neutrophils was clearly reduced; their plasma membrane revealed a profound reduction in the density of intramembrane particles. An interrelationship between reduced particle density and defective chemotaxis in neutrophils is assumed, but not yet proven.

Disorders of phagocyte chemotaxis.

Recent advances in understanding the physiologic and biochemical bases for recruitment of phagocytes to inflammatory sites has led to the recognition of patients who have recurrent infections because of abnormalities of phagocyte chemotaxis. In some of these patients there is abnormal chemoattractant mediator production or regulation, whereas in others there are defects in phagocytic cell function. The cellular defects in chemotaxis can be characterized as either intrinsic defects of the cellular motility apparatus or acquired defects from mediators influencing cell function or from shifts in circulating phagocyte subpopulations. Systematic study of these defects has resulted in functional, biochemical, and ultrastructural characterization of abnormal phagocyte chemotaxis in certain patients, and in some patients study has led to rational approaches for treatment. Clinical trials assessing the efficacy of such pharmacologic agents are underway.

Kartageners syndrome: a report of six cases with special reference to humoral and cellular immunity.

4 men and 2 women presenting with Kartagener's syndrome were studied. Humoral and cellular immunity were evaluated by measuring immunoglobulin levels, total complement activity, C3, C4 and C5 levels, lymphocyte subpopulations, lymphoproliferative response to PHA, delayed hypersensitivity skin reactions and histocompatibility antigens. The in vitro tests for cellular and humoral immunity showed normal results, or only transitory alterations. However, the in vivo tests clearly showed a decrease in the delayed response in the skin tests using bacterial and mycotic antigens and PPD. In two siblings the HLA typing showed identical haplotypes. The results are presented taking into account the new physiopathogenetic concepts of Karagener's syndrome with respect to dysfunction of the ciliated columnar epithelium and chemotactic defects of the nonciliated blood cells found in these patients.