The laminin β1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma

Dekkers, Bart G. J.; Bos, I. Sophie T.; Halayko, Andrew J.; Zaagsma, Johan

doi:10.1186/1465-9921-11-170

Cited by 17 publications

(12 citation statements)

References 46 publications

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“…Various integrins have been implicated to modulate aspects of asthma pathophysiology - airway inflammation 7 , AWR 16 , and AHR 7 . Hence, it has been proposed that integrins are therapeutic targets in asthma.…”

Section: Discussionmentioning

confidence: 99%

Integrin α7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells

Teoh

Tan

Langenbach

et al. 2019

Sci Rep

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Airway smooth muscle (ASM) cells exhibit plastic phenotypic behavior marked by reversible modulation and maturation between contractile and proliferative phenotypic states. Integrins are a class of transmembrane proteins that have been implicated as novel therapeutic targets for asthma treatment. We previously showed that integrin α7 is a novel marker of the contractile ASM phenotype suggesting that targeting this protein may offer new avenues to counter the increase in ASM cell mass that underlies airways hyperresponsiveness (AHR) in asthma. We now determine whether inhibition of integrin α7 expression would revert ASM cells back to a proliferative phenotype to cause an increase in ASM cell mass. This would be detrimental to asthmatic patients who already exhibit increased ASM mass in their airways. Using immunohistochemical analysis of the Melbourne Epidemiological Study of Childhood Asthma (MESCA) cohort, we show for the first time that integrin α7 expression in patients with severe asthma is increased, supporting a clinically relevant role for this protein in asthma pathophysiology. Moreover, inhibition of the laminin-integrin α7 signaling axis results in a reduction in smooth muscle-alpha actin abundance and does not revert ASM cells back to a proliferative phenotype. We determined that integrin α7-induced Kras isoform of p21 Ras acts as a point of convergence between contractile and proliferative ASM phenotypic states. Our study provides further support for targeting integrin α7 for the development of novel anti-asthma therapies.

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Section: Discussionmentioning

confidence: 99%

Integrin α7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells

Teoh

Tan

Langenbach

et al. 2019

Sci Rep

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“…Dekkers et al (21) showed that exogenous laminin sustains a contractile phenotype and prevents proliferation of bovine tracheal smooth muscle cells. Using a guinea pig model of chronic asthma to further explore the role of laminins in ASM remodeling in vivo , the researchers treated the animals with the specific soluble laminin competing peptide YIGSR and showed that YIGSR did inhibit allergen‐induced ASM accumulation (22). However, in contrast to their previous in vitro studies, soluble YIGSR promoted a hypercontractile phenotype.…”

Section: Discussionmentioning

confidence: 99%

Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity

et al. 2013

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Increased airway smooth muscle (ASM) mass is believed to underlie the relatively fixed airway hyperresponsiveness (AHR) in asthma. Developments of therapeutic approaches to reverse airway remodeling are impeded by our lack of insight on the mechanisms behind the increase in mass of contractile ASM cells. Increased expression of laminin, an extracellular matrix protein, is associated with asthma. Our studies investigate the role of laminin-induced ASM survival signals in the development of increased ASM and AHR. Antagonizing laminin integrin binding using the laminin-selective competing peptide, YIGSR, and mimicking laminin with exogenous α2-chain laminin, we show that laminin is both necessary and sufficient to induce ASM cell survival, concomitant with the induction of ASM contractile phenotype. Using siRNA, we show that the laminin-binding integrin α7β1 mediates this process. Moreover, in laminin-211-deficient mice, allergen-induced AHR was not observed. Notably, ASM cells from asthmatic airways express a higher abundance of intracellular cell survival proteins, consistent with a role for reduced rates of cell apoptosis in development of ASM hyperplasia. Targeting the laminin-integrin α7β1 signaling pathway may offer new avenues for the development of therapies to reduce the increase in mass of contractile phenotype ASM cells that underlie AHR in asthma.

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“…Guinea pigs have also been sensitized systemically to OVA by using alum as an adjuvant and were subsequently challenged with OVA aerosol for up to 12 weeks, which resembles protocols from mouse models of chronic experimental asthma. Such a protocol results in profound allergic airway inflammation associated with goblet cell hyperplasia, mucus gland hypertrophy, smooth muscle layer thickening and increased collagen deposition (Dekkers et al 2010 ; Maarsingh et al 2011 ; Lucarini et al 2014 ).…”

Section: Animal Models In the Study Of Airway Remodelingmentioning

confidence: 99%

Airway remodeling in asthma: what really matters

2017

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Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and “endotyped” human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

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The laminin β1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma

Cited by 17 publications

References 46 publications

Integrin α7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells

Integrin α7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells

Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity

Airway remodeling in asthma: what really matters

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