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

Acute mucin secretion does not cause AHRWT mice were OVA or PBS challenged, and then anesthetized, ventilated, and exposed to UTP (0.1-100 mg/ml) or vehicle (saline). (a) In OVA challenged lungs fixed immediately after dose response tests, there was an acute decrease in periodic acid fluorescent Schiff’s (PAFS) staining in UTP (right panel) compared to vehicle (‘-UTP’, left panel) treated mice, demonstrating acute UTP-induced secretion. Scale bars, 20 μm. (b) Quantitation of UTP-induced changes in PAFS staining in OVA challenged mice. (c) No effect of UTP on RL in either PBS or OVA challenged WT mice. Mean, s.e.m. in b and c. Numbers in parentheses, ‘N’ mice. ‘Vol.’, volume. Dashed line in b, baseline in saline challenged WT mice. ‘*’, p < 0.05 by t Test.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4333679&req=5

Figure 4: Acute mucin secretion does not cause AHRWT mice were OVA or PBS challenged, and then anesthetized, ventilated, and exposed to UTP (0.1-100 mg/ml) or vehicle (saline). (a) In OVA challenged lungs fixed immediately after dose response tests, there was an acute decrease in periodic acid fluorescent Schiff’s (PAFS) staining in UTP (right panel) compared to vehicle (‘-UTP’, left panel) treated mice, demonstrating acute UTP-induced secretion. Scale bars, 20 μm. (b) Quantitation of UTP-induced changes in PAFS staining in OVA challenged mice. (c) No effect of UTP on RL in either PBS or OVA challenged WT mice. Mean, s.e.m. in b and c. Numbers in parentheses, ‘N’ mice. ‘Vol.’, volume. Dashed line in b, baseline in saline challenged WT mice. ‘*’, p < 0.05 by t Test.

Mentions: Because acute mucin secretion was required for AHR to MCh with no residual effect attributable to ASM hypercontractility (Figs. 2 and 3), we next determined whether mucin secretion was sufficient to acutely induce AHR independently of bronchoconstriction. In airway epithelial cells, P2Y2 purinergic receptor stimulation is a major pathway for mucin secretion40. P2Y2 receptors are activated by the endogenous agonists ATP and UTP40,41. ATP is rapidly dephosphorylated to adenosine, a signaling molecule that itself induces bronchoconstriction; ATP was thus inappropriate for these studies. Since UTP and its metabolites do not cause acute ASM contraction42, we challenged WT C57BL/6 mice with OVA or saline, and 72 h later we mechanically ventilated them and measured immediate changes in secretion and lung resistance in response to UTP. In OVA challenged WT mice, although UTP rapidly stimulated secretion (Figs. 4a,b), there was no disruption of airflow (Fig. 4c). Thus, although Muc5ac was critical for allergic AHR in the presence of ASM-mediated bronchoconstriction following MCh, UTP-induced mucin secretion alone did not evoke an AHR response.


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)

Acute mucin secretion does not cause AHRWT mice were OVA or PBS challenged, and then anesthetized, ventilated, and exposed to UTP (0.1-100 mg/ml) or vehicle (saline). (a) In OVA challenged lungs fixed immediately after dose response tests, there was an acute decrease in periodic acid fluorescent Schiff’s (PAFS) staining in UTP (right panel) compared to vehicle (‘-UTP’, left panel) treated mice, demonstrating acute UTP-induced secretion. Scale bars, 20 μm. (b) Quantitation of UTP-induced changes in PAFS staining in OVA challenged mice. (c) No effect of UTP on RL in either PBS or OVA challenged WT mice. Mean, s.e.m. in b and c. Numbers in parentheses, ‘N’ mice. ‘Vol.’, volume. Dashed line in b, baseline in saline challenged WT mice. ‘*’, p < 0.05 by t Test.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Acute mucin secretion does not cause AHRWT mice were OVA or PBS challenged, and then anesthetized, ventilated, and exposed to UTP (0.1-100 mg/ml) or vehicle (saline). (a) In OVA challenged lungs fixed immediately after dose response tests, there was an acute decrease in periodic acid fluorescent Schiff’s (PAFS) staining in UTP (right panel) compared to vehicle (‘-UTP’, left panel) treated mice, demonstrating acute UTP-induced secretion. Scale bars, 20 μm. (b) Quantitation of UTP-induced changes in PAFS staining in OVA challenged mice. (c) No effect of UTP on RL in either PBS or OVA challenged WT mice. Mean, s.e.m. in b and c. Numbers in parentheses, ‘N’ mice. ‘Vol.’, volume. Dashed line in b, baseline in saline challenged WT mice. ‘*’, p < 0.05 by t Test.
Mentions: Because acute mucin secretion was required for AHR to MCh with no residual effect attributable to ASM hypercontractility (Figs. 2 and 3), we next determined whether mucin secretion was sufficient to acutely induce AHR independently of bronchoconstriction. In airway epithelial cells, P2Y2 purinergic receptor stimulation is a major pathway for mucin secretion40. P2Y2 receptors are activated by the endogenous agonists ATP and UTP40,41. ATP is rapidly dephosphorylated to adenosine, a signaling molecule that itself induces bronchoconstriction; ATP was thus inappropriate for these studies. Since UTP and its metabolites do not cause acute ASM contraction42, we challenged WT C57BL/6 mice with OVA or saline, and 72 h later we mechanically ventilated them and measured immediate changes in secretion and lung resistance in response to UTP. In OVA challenged WT mice, although UTP rapidly stimulated secretion (Figs. 4a,b), there was no disruption of airflow (Fig. 4c). Thus, although Muc5ac was critical for allergic AHR in the presence of ASM-mediated bronchoconstriction following MCh, UTP-induced mucin secretion alone did not evoke an AHR response.

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