Airway hyperresponsiveness in asthma: the role of the epithelium

Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze and chest tightness. Dysfunctional airway smooth muscle (ASM) significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacological bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma, through the release of cytokines such as TSLP and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D2 and cysteine leukotrienes. While bronchoconstriction is largely due to ASM constriction, airway structural changes termed 'remodelling', likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine

Effects of deep inspirations (DI) in healthy mice; () lung resistance (R) in mice given incremental doses of methacholine (MCH group), and () the effect of DI on lung compliance (C) presented as ΔC

Values are mean ± SEM, * < 0.05, ** < 0.01, *** < 0.001.<p><b>Copyright information:</b></p><p>Taken from "Different effects of deep inspirations on central and peripheral airways in healthy and allergen-challenged mice"</p><p>http://respiratory-research.com/content/9/1/23</p><p>Respiratory Research 2008;9(1):23-23.</p><p>Published online 28 Feb 2008</p><p>PMCID:PMC2291047.</p><p></p

Representative histological sections (hematoxylin and eosin stained) from healthy control animals in the PBS'98 group (picture A and B) and from animals having undergone a 98-day ovalbumin challenge protocol, the OVA'98 group (picture C and D)

Examination of sections from OVA'98 animals revealed a significant inflammation surrounding the airways and within the alveolar spaces. PBS'98 did not show any signs of inflammation.<p><b>Copyright information:</b></p><p>Taken from "Different effects of deep inspirations on central and peripheral airways in healthy and allergen-challenged mice"</p><p>http://respiratory-research.com/content/9/1/23</p><p>Respiratory Research 2008;9(1):23-23.</p><p>Published online 28 Feb 2008</p><p>PMCID:PMC2291047.</p><p></p

Airway hyperresponsiveness in asthma: the role of the epithelium

Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze and chest tightness. Dysfunctional airway smooth muscle (ASM) significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacological bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma, through the release of cytokines such as TSLP and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D2 and cysteine leukotrienes. While bronchoconstriction is largely due to ASM constriction, airway structural changes termed 'remodelling', likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine

Poly(I:C) and LPS induced cytokine release in BALF.

<p>Levels of (A) IL-5, (B) IL-12, (C) MCP-1, (D) KC, (E) MIG and (F) VEGF in BALB/c mice treated during 4 days with vehicle (white), poly(I:C) (black) or LPS (gray) i.n. Results are expressed as mean ± SEM. PBS n = 10; poly I:C n = 12; LPS n = 13; ***p<0.001.</p

Poly(I:C) and LPS induced cell recruitment in BALF.

<p>(A, C) Absolute and (B, D) relative cell numbers in BALF in BALB/c mice (A, B) respectively MyD88deficient C57BL/6 mice (C, D) treated during 4 days with vehicle (PBS), poly(I:C) or LPS i.n.. Results are expressed as mean ± SEM. *p<0.05.</p

LPS and poly(I:C) induced airway hyperresponsiveness.

<p>(A) Changes in lung resistance (R_L) and (B) compliance (C_L) in response to methacholine in BALB/c mice treated during 4 days with vehicle (PBS), poly(I:C) or LPS i.n.. Results are expressed as mean ± SEM. *p<0.05, ***p<0.001 vs. PBS.</p

Poly(I:C) and LPS induced cell recruitment in lung tissue.

<p>Haematoxylin and eosin stained cells in BALB/c mice treated i.n. during 4 days with (A) vehicle, (B) poly(I:C) (mainly neutrophils) and (C) LPS (mainly lymphocytes). Magnification is ×200. (D) Semi quantitative grading score of cell infiltration in the lung.</p

Inflammatory mediators in BALF following TLR ligand challenge in OVA-sensitised mice.

<p>All animals were sensitised i.p. with OVA/Al (OH)₃ and subsequently challenged i.n. with PBS or OVA (3 days) and PBS, LPS or Poly (I:C) (4 days). 24 hrs after the final challenge, BALF was extracted and cytokine levels were measured using the Cytokine Mouse 20-Plex Panel and the RANTES Mouse Singleplex Bead Kit. Data is represented as mean ± SEM. Data was analysed using a two-way ANOVA followed by a Bonferroni multiple comparison post-test *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. n = 6–14 animals per group.</p

Airway hyperresponsiveness in OVA-sensitised and challenged mice treated with LPS or poly (I:C).

<p>All animals were sensitised i.p. with OVA/Al (OH)₃ and subsequently challenged i.n. with PBS or OVA (3 days) and PBS, LPS or Poly (I:C) (4 days). 24 hrs after the final challenge, changes in lung resistance (R_L) in response to increasing doses of methacholine (MCh) was measured using the flexiVent animal respirator. Data is represented as mean resistance (R_L) ± SEM. (A) Animals were treated with PBS or LPS for 4 days following OVA or PBS treatment. (B) Animals were treated with PBS or Poly (I:C) for 4 days following OVA or PBS treatment. ¤ p<0.05 comparing EC₅₀ values between OVA-PBS and OVA-LPS or OVA-PBS and OVA-Poly (I:C) using one-way ANOVA followed by a Tukey multiple-comparison post-test. ****p<0.0001 comparing R_Lmax of OVA and PBS challenged groups (OVA-PBS vs. PBS-PBS; OVA-LPS vs. PBS-LPS; OVA-Poly (I:C) vs. PBS-Poly (I:C)) using one-way ANOVA followed by a Tukey multiple-comparison post-test. n = 13–16 animals per group.</p