Autopsy and Imaging Studies of Mucus in Asthma. Lessons Learned about Disease Mechanisms and the Role of Mucus in Airflow Obstruction

Abstract

Autopsy studies in fatal asthma have clearly documented the central role of airway plugging with pathologic mucus in the pathophysiology of death from asthma, but the role of mucus plugs in chronic severe asthma has been less well understood. Recently, multidetector computerized tomography imaging of the lungs has emerged as a valuable method to visualize mucus plugs in asthma. These multidetector computerized tomography data have revealed mucus plugs as a common occurrence in severe forms of asthma. In addition, an image-based mucus plug scoring system shows that mucus plugs are strongly associated with measures of airflow obstruction and with biomarkers of type 2 cytokine and eosinophilic inflammation. These data provide a rationale for treating airflow obstruction in severe asthma with mucolytics, and they also raise the possibility that treatments that target type 2 inflammation may decrease mucus plugs in asthma.

Keywords: eosinophil peroxidase; eosinophils; mucins; type 2 inflammation.

Figure 1.

Bronchial casts in asthma. Bronchial casts recovered from the bronchoalveolar lavage of a patient experiencing an acute exacerbation. High concentrations of albumin are found in the airway mucus in acute severe asthma. Reprinted by permission from Reference .

Figure 2.

Mucus plugs contribute to airflow obstruction in acute severe asthma. Gross specimen of lungs removed from a patient with fatal asthma. The lungs fail to remain inflated despite loss of negative intrathoracic pressure and fail to deflate when pressed as a result of air trapping from intraluminal mucus plugs. Reprinted by permission from Reference .

Figure 3.

Negative pressure silicone casts of the airways. (A) Cast of the apical segment left lower lobe from a healthy control subject shown in greater detail in B. (C) Cast of a patient who died of asthma showing widespread loss of large airways (arrows) and (D) enlarged mucus glands on higher power. (E) Cast of a patient who died with asthma from nonasthma cause, showing loss of smaller airway, with (F) enlarged mucus glands on higher power. Reprinted by permission from Reference .

Figure 4.

Mucus plugs shown in different planes on multidetector computed tomography. (A) Intraluminal mucus plug (red arrow) in longitudinal section on transverse plane. The accompanying bronchopulmonary vessels are indicated with yellow asterisks. (B) The same mucus plug seen on the sagittal plane (red arrow) demonstrates continuity with a patent airway lumen (green arrow) visible proximally. Reprinted by permission from Reference .

Figure 5.

High mucus score is associated with airflow obstruction. Forced expiratory volume in 1 second (FEV₁)% predicted in patients with a high mucus score was significantly lower than in subjects with a low mucus score and patients with a zero mucus score before and after maximal bronchodilation reversibility testing. ***Indicates P < 0.001. Reprinted by permission from Reference .

Figure 6.

High mucus score is associated with airway type 2 inflammation. (A) Percent sputum eosinophils were significantly higher in patients with a high mucus score before and after treatment with intramuscular triamcinolone. (B) Sputum cell gene expression of IL-13 was significantly higher in patients with a high mucus score before and after treatment with intramuscular triamcinolone. (C) Sputum cell gene expression of IL-5 in patients was significantly higher in patients with a high mucus score before and after treatment with intramuscular triamcinolone. *P < 0.05; **P < 0.01; ***P < 0.001. Reprinted by permission from Reference .

Figure 7.

Schematic representation of the components of a generic mucin glycoprotein. The mucin monomer typically consists of cysteine-rich NH3- and -COOH termini (red) and one or more central domain(s) (green/blue). The central domains contain heavily glycosylated proteins (green) interspersed with internal cysteine domains (blue). The N- and C-terminal domains form disulfide bonds with other mucin monomers end-to-end to form long polymers. Internal cysteines form disulfide bonds with other mucin polymers side-to-side to form a complex entangled three-dimensional mesh, which is the basis of the elastic properties of mucus gel.

Figure 8.

Conceptual model for eosinophils promoting mucus plug formation in asthma. Epithelium, stimulated by IL-13, secretes high concentrations of mucin, particularly cysteine-rich MUC5AC mucin, into the airway lumen. IL-13 also increases transport of thiocyanate into the airway lumen through the ion exchanger pendrin. High levels of IL-5 promote survival of these eosinophils. On activation, eosinophils release eosinophil peroxidase and hydrogen peroxide that react with thiocyanate to promote crosslinking of mucins and mucus gel stiffening through cysteine oxidation and disulfide bond formation.