Cigarette Smoke–Induced Damage-Associated Molecular Pattern Release from Necrotic Neutrophils Triggers Proinflammatory Mediator Release

Abstract

Cigarette smoking, the major causative factor for the development of chronic obstructive pulmonary disease, is associated with neutrophilic airway inflammation. Cigarette smoke (CS) exposure can induce a switch from apoptotic to necrotic cell death in airway epithelium. Therefore, we hypothesized that CS promotes neutrophil necrosis with subsequent release of damage-associated molecular patterns (DAMPs), including high mobility group box 1 (HMGB1), alarming the innate immune system. We studied the effect of smoking two cigarettes on sputum neutrophils in healthy individuals and of 5-day CS or air exposure on neutrophil counts, myeloperoxidase, and HMGB1 levels in bronchoalveolar lavage fluid of BALB/c mice. In human peripheral blood neutrophils, mitochondrial membrane potential, apoptosis/necrosis markers, caspase activity, and DAMP release were studied after CS exposure. Finally, we assessed the effect of neutrophil-derived supernatants on the release of chemoattractant CXCL8 in normal human bronchial epithelial cells. Cigarette smoking caused a significant decrease in sputum neutrophil numbers after 3 hours. In mice, neutrophil counts were significantly increased 16 hours after repeated CS exposure but reduced 2 hours after an additional exposure. In vitro, CS induced necrotic neutrophil cell death, as indicated by mitochondrial dysfunction, inhibition of apoptosis, and DAMP release. Supernatants from CS-treated neutrophils significantly increased the release of CXCL8 in normal human bronchial epithelial cells. Together, these observations show, for the first time, that CS exposure induces neutrophil necrosis, leading to DAMP release, which may amplify CS-induced airway inflammation by promoting airway epithelial proinflammatory responses.

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

“…The smoking-induced chronic, smoldering inflammation in the lung leads to a tolerance break and altered immunity. Kearley et al recently focused on a smoking-induced IL-33-dependent proinflammatory response (100), Yuan F. et al (101) showed that cigarette smoke extract causes macrophage M2 polarization and Heijink IH et al (102) reported that cigarette smoke promotes neutrophil necrosis. In our opinion there is a need to investigate the pathobiology of cigarette smoke-inhalation—related pulmonary vascular diseases and to consider in addition to direct toxic endothelial cell effects also aberrant immune responses.…”

A prototypic modified risk tobacco product exhibits reduced effects on chemotaxis and transendothelial migration of monocytes compared with a reference cigarette

“…The release of damageassociated molecular pattern (DAMP) molecules from dying cells may amplify CS-induced vascular inflammation by promotion of additional proinflammatory responses (Sangiuliano et al, 2014). It should be noted that CS has been recently shown to promote neutrophil necrosis and the subsequent release of DAMPs including highmobility group box 1 protein (Heijink et al, 2014).…”

Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients

“…As a consequence of the inflammation microenvironment and massive cell death induced by HPV or smoking, chronic inflammation occurs [14,26,28,29] . Increasing inflammation-related proteins, CRP and cytokines, and TNFα in the plasma of H&N cancer patients supported our assumption [12] .…”