Limits...
The polymeric mucin Muc5ac is required for allergic airway hyperreactivity.

Evans CM, Raclawska DS, Ttofali F, Liptzin DR, Fletcher AA, Harper DN, McGing MA, McElwee MM, Williams OW, Sanchez E, Roy MG, Kindrachuk KN, Wynn TA, Eltzschig HK, Blackburn MR, Tuvim MJ, Janssen WJ, Schwartz DA, Dickey BF - Nat Commun (2015)

Bottom Line: However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective.Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism.Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Colorado School of Medicine, 12700 E 19th Avenue, Mailstop 8611, Research Complex 2, Room 3121, Aurora, Colorado 80045, USA.

ABSTRACT
In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

No MeSH data available.


Related in: MedlinePlus

Muc5ac is required for AHR to MChLung resistance (RL) responses to MCh in WT (+/+, black), Muc5ac+/- (turquoise), and Muc5ac−/− (magenta) mice after saline (open circles), OVA (closed circles in a), or Aspergillus oryzae extract (AOE; closed circles in b and c). Mean, s.e.m. (a-c). ‘*’, p<0.05 between slopes of best-fit regression lines by one-way ANOVA. Numbers in parentheses, ‘N’ mice.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4333679&req=5

Figure 2: Muc5ac is required for AHR to MChLung resistance (RL) responses to MCh in WT (+/+, black), Muc5ac+/- (turquoise), and Muc5ac−/− (magenta) mice after saline (open circles), OVA (closed circles in a), or Aspergillus oryzae extract (AOE; closed circles in b and c). Mean, s.e.m. (a-c). ‘*’, p<0.05 between slopes of best-fit regression lines by one-way ANOVA. Numbers in parentheses, ‘N’ mice.

Mentions: To determine the consequences of disrupting Muc5ac expression on airflow obstruction, we assessed lung mechanical function and AHR to MCh. OVA challenge did not alter baseline lung resistance (Supplementary Fig. 1a), demonstrating that inflammatory and mucous metaplastic changes did not disrupt steady state airflow measurably in this model of late-phase asthma. However, when exposed to MCh, OVA challenged WT and heterozygous mice both demonstrated significant AHR. By contrast, Muc5ac−/− mice were protected (Fig. 2a and Supplementary Fig. 1b). To confirm these findings, we also assessed AHR in C57BL/6 and BALB/c WT and congenic Muc5ac−/− mice exposed to aerosolized Aspergillus oryzae extract (AOE). AOE is a fungal allergen pertinent to human asthma that upon mucosal sensitization elicits strong asthma-like responses in mice38. In WT animals, AOE challenge caused AHR to MCh, but in both Muc5ac−/− lines, AHR was abolished (Figs. 2b,c and Supplementary Fig. 1b). Importantly, protection occurred irrespective of C57BL/6 and BALB/c strain-specific airway and tissue localized pathophysiologies. To partition AHR on airway and tissue scales, we assessed lung mechanics by measuring input impedance. As reported previously39, AHR was strongly influenced by tissue resistance and elastance in C57BL/6 mice (Figs. 3a and Supplementary Fig. 2) and by tissue and central airway resistance in BALB/c mice (Figs. 3b and Supplementary Fig. 2); Muc5ac deficiency was protective irrespective of background strain. Thus, in diverse models of allergic asthma, Muc5ac was required for AHR to MCh.


The polymeric mucin Muc5ac is required for allergic airway hyperreactivity.

Evans CM, Raclawska DS, Ttofali F, Liptzin DR, Fletcher AA, Harper DN, McGing MA, McElwee MM, Williams OW, Sanchez E, Roy MG, Kindrachuk KN, Wynn TA, Eltzschig HK, Blackburn MR, Tuvim MJ, Janssen WJ, Schwartz DA, Dickey BF - Nat Commun (2015)

Muc5ac is required for AHR to MChLung resistance (RL) responses to MCh in WT (+/+, black), Muc5ac+/- (turquoise), and Muc5ac−/− (magenta) mice after saline (open circles), OVA (closed circles in a), or Aspergillus oryzae extract (AOE; closed circles in b and c). Mean, s.e.m. (a-c). ‘*’, p<0.05 between slopes of best-fit regression lines by one-way ANOVA. Numbers in parentheses, ‘N’ mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4333679&req=5

Figure 2: Muc5ac is required for AHR to MChLung resistance (RL) responses to MCh in WT (+/+, black), Muc5ac+/- (turquoise), and Muc5ac−/− (magenta) mice after saline (open circles), OVA (closed circles in a), or Aspergillus oryzae extract (AOE; closed circles in b and c). Mean, s.e.m. (a-c). ‘*’, p<0.05 between slopes of best-fit regression lines by one-way ANOVA. Numbers in parentheses, ‘N’ mice.
Mentions: To determine the consequences of disrupting Muc5ac expression on airflow obstruction, we assessed lung mechanical function and AHR to MCh. OVA challenge did not alter baseline lung resistance (Supplementary Fig. 1a), demonstrating that inflammatory and mucous metaplastic changes did not disrupt steady state airflow measurably in this model of late-phase asthma. However, when exposed to MCh, OVA challenged WT and heterozygous mice both demonstrated significant AHR. By contrast, Muc5ac−/− mice were protected (Fig. 2a and Supplementary Fig. 1b). To confirm these findings, we also assessed AHR in C57BL/6 and BALB/c WT and congenic Muc5ac−/− mice exposed to aerosolized Aspergillus oryzae extract (AOE). AOE is a fungal allergen pertinent to human asthma that upon mucosal sensitization elicits strong asthma-like responses in mice38. In WT animals, AOE challenge caused AHR to MCh, but in both Muc5ac−/− lines, AHR was abolished (Figs. 2b,c and Supplementary Fig. 1b). Importantly, protection occurred irrespective of C57BL/6 and BALB/c strain-specific airway and tissue localized pathophysiologies. To partition AHR on airway and tissue scales, we assessed lung mechanics by measuring input impedance. As reported previously39, AHR was strongly influenced by tissue resistance and elastance in C57BL/6 mice (Figs. 3a and Supplementary Fig. 2) and by tissue and central airway resistance in BALB/c mice (Figs. 3b and Supplementary Fig. 2); Muc5ac deficiency was protective irrespective of background strain. Thus, in diverse models of allergic asthma, Muc5ac was required for AHR to MCh.

Bottom Line: However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective.Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism.Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Colorado School of Medicine, 12700 E 19th Avenue, Mailstop 8611, Research Complex 2, Room 3121, Aurora, Colorado 80045, USA.

ABSTRACT
In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

No MeSH data available.


Related in: MedlinePlus