Near Fatal Asthma: Clinical and Airway Biopsy Characteristics

Barbers, Richard G.; Papanikolaou, Ilias; Koss, Michael N.; Patel, Ashish; Katagihara, Elton; Arenas, Maggie; Chan, Khalid; Azen, Colleen; Sharma, Om P.

doi:10.1155/2012/829608

Cited by 5 publications

(4 citation statements)

References 20 publications

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“…In asthma, the airway wall thickens in proportion to disease severity and duration 50,51 . This remodelling involves an increase in airway smooth muscle, thickening of the subepithelial reticular lamina, matrix deposition throughout the airway wall, angiogenesis, neuronal proliferation and epithelial mucous metaplasia -a process that involves the appearance of mucous cells in new areas of the airways and increased production of mucus (FIG.…”

Section: Airway Remodellingmentioning

confidence: 99%

Asthma

Holgate

Wenzel

Postma

et al. 2015

Nat Rev Dis Primers

514

408

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Asthma is the most common inflammatory disease of the lungs. The prevalence of asthma is increasing in many parts of the world that have adopted aspects of the Western lifestyle, and the disease poses a substantial global health and economic burden. Asthma involves both the large-conducting and the small-conducting airways, and is characterized by a combination of inflammation and structural remodelling that might begin in utero. Disease progression occurs in the context of a developmental background in which the postnatal acquisition of asthma is strongly linked with allergic sensitization. Most asthma cases follow a variable course, involving viral-induced wheezing and allergen sensitization, that is associated with various underlying mechanisms (or endotypes) that can differ between individuals. Each set of endotypes, in turn, produces specific asthma characteristics that evolve across the lifecourse of the patient. Strong genetic and environmental drivers of asthma interconnect through novel epigenetic mechanisms that operate prenatally and throughout childhood. Asthma can spontaneously remit or begin de novo in adulthood, and the factors that lead to the emergence and regression of asthma, irrespective of age, are poorly understood. Nonetheless, there is mounting evidence that supports a primary role for structural changes in the airways with asthma acquisition, on which altered innate immune mechanisms and microbiota interactions are superimposed. On the basis of the identification of new causative pathways, the subphenotyping of asthma across the lifecourse of patients is paving the way for more-personalized and precise pathway-specific approaches for the prevention and treatment of asthma, creating the real possibility of total prevention and cure for this chronic inflammatory disease.

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Section: Airway Remodellingmentioning

confidence: 99%

Asthma

Holgate

Wenzel

Postma

et al. 2015

Nat Rev Dis Primers

514

408

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“…This situation differs from that of conventional asthma, which is characterized by eosinophil infiltration [12,13]. Neutrophil elastase (NE) generated by neutrophils has been shown to be a potent mucin secretagogue [14].…”

Section: Introductionmentioning

confidence: 99%

Ezrin/Exocyst Complex Regulates Mucin 5AC Secretion Induced by Neutrophil Elastase in Human Airway Epithelial Cells

Liu

et al. 2015

Cell Physiol Biochem

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Background/Aim: Increased mucin secretion is a characteristic feature of many chronic airway diseases, particularly during periods of exacerbation; however, the exact mechanism of mucin secretion remains unclear. Ezrin, which is a specific marker of apical membranes, is predominantly concentrated in exocyst-rich cell surface structures, crosslinking the actin cytoskeleton with the plasma membrane. In the present study, we examined whether Ezrin is involved in mucin 5AC (MUC5AC) secretion after neutrophil elastase (NE) attack, and we investigated the role of the exocyst complex docking protein Sec3 in this process. Methods: NE was used as a stimulator in a 16HBE14o- cell culture model. The expression and location of Ezrin and Sec3 were investigated, and the interaction between Ezrin and Sec3 in 16HBE14o-cells was assayed after treatment with NE, Ezrin siRNA, Sec3 siRNA, neomycin or PIP2-Ab. Results: We found that Ezrin was highly expressed in the bronchi of humans with chronic airway diseases. NE induced robust MUC5AC protein secretion. The Ezrin siRNA, Sec3 siRNA, and neomycin treatments led to impaired MUC5AC secretion in cells. Both Ezrin and Sec3 were recruited primarily to the cytoplasmic membrane after NE stimulation, and the neomycin and PIP2-Ab treatments abrogated this effect. Immunoprecipitation analysis revealed that Ezrin and Sec3 combined to form complexes; however, these complexes could not be detected in Ezrin_∆_1-333 mutant-transfected cells, even when PIP2 was added. Conclusions: These results demonstrate that Ezrin/Sec3 complexes are essential for MUC5AC secretion in NE-stimulated airway epithelial cells and that PIP2 is of critical importance in the formation of these complexes.

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“…16 Studies of fatal or near-fatal asthma have indicated that increased inflammation during exacerbations aggravates this chronic state, causing pronounced mucus oedema, and lumen occlusion by mucus plugs, in a setting of predominantly eosinophilic infiltration. [17][18][19] In light of this, even subtle changes in oxygenation could represent differences in the pathology involved and prove to be of prognostic value, but further studies are required to investigate this.…”

Section: Discussionmentioning

confidence: 99%

“…Eosinophilic airway inflammation is associated with more pronounced airway smooth muscle hypertrophy, and severe asthma in general is known to be associated with pronounced structural changes in the peripheral airways . Studies of fatal or near‐fatal asthma have indicated that increased inflammation during exacerbations aggravates this chronic state, causing pronounced mucus oedema, and lumen occlusion by mucus plugs, in a setting of predominantly eosinophilic infiltration . In light of this, even subtle changes in oxygenation could represent differences in the pathology involved and prove to be of prognostic value, but further studies are required to investigate this.…”

Section: Discussionmentioning

confidence: 99%