Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients

Powell, Jason, Garnett, James, Mather, Michael W., Cooles, Faye A. H., Nelson, Andrew, Verdon, Bernard, Scott, Jon, Jiwa, Kasim, Ruchaud-Sparagano, Marie-Hélène, Cummings, Stephen, Perry, John, Wright, Stephen, Wilson, Janet, Pearson, Jeffrey, Ward, Chris and Simpson, A. John (2018) Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients. American Journal of Respiratory and Critical Care Medicine. ISSN 1073-449X

Preview

Text (Full text) Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients_.pdf - Submitted Version Download (1MB) | Preview

Abstract

Rationale:
Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP.

Objectives:
To characterize subglottic host defense dysfunction in mechanically ventilated patients in the intensive care unit (ICU). To determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth.

Methods:
Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 minutes). Isolation and culture of primary subglottic epithelial cells from controls. Laboratory analysis of host innate immune defenses.

Measurements and Main Results:
Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in ICU was characterized by neutrophilic inflammation, significantly increased pro-inflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic function was reversible upon treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium.

Conclusions:
Mechanical ventilation in ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil dysfunction and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage.

Actions (login required)

View Item

Downloads