Genetic Variation in Surfactant Protein-A2 Results in Altered Regulation of Eosinophil Activities and Enhanced Eosinophilia in Patients with Asthma

Ledford, Julie G.; Addison, Kenneth J.; Francisco, Dave; Foster, Matthew W.; Voelker, Dennis R.; Que, Loretta G.; Kraft, Monica

doi:10.1513/annalsats.201508-520mg

Cited by 2 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because Alcian Blue can also stain basal lamina matrix proteins, staining at the basal lamina was not considered positive. Evaluation of mucus production using PAS staining was performed by scoring sections on a scale of 1–5, based on extent of staining of epithelial layer and bronchiole lumen indicative of mucus plugs as described (Ledford et al, 2016). In these samples, a score of 1 represented diffuse mucus staining in the epithelial layer; a score of 2–3 indicated increased mucus staining in the epithelial layer; a score of 4 reflected complete epithelial staining and additional mucus staining in the lumen; and a score of 5 reflected complete lumen staining of mucus and full mucus plug of large lumens or multiple smaller lumens as described previously.…”

Section: Methodsmentioning

confidence: 99%

Proteinase‐activated receptor‐2 antagonist C391 inhibits Alternaria‐induced airway epithelial signalling and asthma indicators in acute exposure mouse models

Rivas

Yee

Addison

et al. 2022

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and Purpose Despite the availability of a variety of treatment options, many asthma patients have poorly controlled disease with frequent exacerbations. Proteinase‐activated receptor‐2 (PAR2) has been identified in preclinical animal models as important to asthma initiation and progression following allergen exposure. Proteinase activation of PAR2 raises intracellular Ca2+, inducing MAPK and β‐arrestin signalling in the airway, leading to inflammatory and protective effects. We have developed C391, a potent PAR2 antagonist effective in blocking peptidomimetic‐ and trypsin‐induced PAR2 signalling in vitro as well as reducing inflammatory PAR2‐associated pain in vivo. We hypothesized that PAR2 antagonism by C391 would attenuate allergen‐induced acutely expressed asthma indicators in murine models. Experimental Approach We evaluated the ability of C391 to alter Alternaria alternata‐induced PAR2 signalling pathways in vitro using a human airway epithelial cell line that naturally expresses PAR2 (16HBE14o−) and a transfected embryonic cell line (HEK 293). We next evaluated the ability for C391 to reduce A. alternata‐induced acutely expressed asthma indicators in vivo in two murine strains. Key Results C391 blocked A. alternata‐induced, PAR2‐dependent Ca2+ and MAPK signalling in 16HBE14o− cells, as well as β‐arrestin recruitment in HEK 293 cells. C391 effectively attenuated A. alternata‐induced inflammation, mucus production, mucus cell hyperplasia and airway hyperresponsiveness in acute allergen‐challenged murine models. Conclusions and Implications To our best knowledge, this is the first demonstration of pharmacological intervention of PAR2 to reduce allergen‐induced asthma indicators in vivo. These data support further development of PAR2 antagonists as potential first‐in‐class allergic asthma drugs.

show abstract

Section: Methodsmentioning

confidence: 99%

Proteinase‐activated receptor‐2 antagonist C391 inhibits Alternaria‐induced airway epithelial signalling and asthma indicators in acute exposure mouse models

Rivas

Yee

Addison

et al. 2022

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

Genetic variation in surfactant protein-A2 alters responses to ozone

et al. 2021

View full text Add to dashboard Cite

Background Increased exposure to Ozone (O3) is associated with adverse health effects in individuals afflicted with respiratory diseases. Surfactant protein-A (SP-A), encoded by SP-A1 and SP-A2, is the largest protein component in pulmonary surfactant and is functionally impaired by O3-oxidation. Objective We used humanized SP-A2 transgenic mice with allelic variation corresponding to a glutamine (Q) to lysine (K) amino acid substitution at position 223 in the lectin domain to determine the impact of this genetic variation in regards to O3 exposure. Methods Mice were exposed to 2ppm O3 or Filtered Air (FA) for 3 hours and 24 hrs post-challenge pulmonary function tests and other parameters associated with inflammation were assessed in the bronchoalveolar lavage (BAL) fluid and lung tissue. Additionally, mouse tracheal epithelial cells were cultured and TEER measurements recorded for each genotype to determine baseline epithelial integrity. Results Compared to FA, O3 exposure led to significantly increased sensitivity to methacholine challenge in all groups of mice. SP-A2 223Q variant mice were significantly protected from O3-induced AHR compared to SP-A-/- and SP-A2 223K mice. Neutrophilia was observed in all genotypes of mice post O3-exposure, however, SP-A2 223Q mice had a significantly lower percentage of neutrophils compared to SP-A-/- mice. Albumin levels in BAL were unchanged in O3-exposed SP-A2 223Q mice compared to their FA controls, while levels were significantly increased in all other genotypes of O3-exposed mice. SP-A 223Q MTECS has significant higher TEER values than all other genotypes, and WT MTECS has significantly higher TEER than the SP-A KO and SP-A 223K MTECS. Significance Taken together, our study suggests that expression of a glutamine (Q) as position 223 in SP-A2, as opposed to expression of lysine (K), is more protective in acute exposures to ozone and results in attenuated O3-induced AHR, neutrophilia, and vascular permeability.

show abstract

Genetic Variation in Surfactant Protein-A2 Results in Altered Regulation of Eosinophil Activities and Enhanced Eosinophilia in Patients with Asthma

Cited by 2 publications

References 0 publications

Proteinase‐activated receptor‐2 antagonist C391 inhibits Alternaria‐induced airway epithelial signalling and asthma indicators in acute exposure mouse models

Proteinase‐activated receptor‐2 antagonist C391 inhibits Alternaria‐induced airway epithelial signalling and asthma indicators in acute exposure mouse models

Genetic variation in surfactant protein-A2 alters responses to ozone

Contact Info

Product

Resources

About