Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection

Abstract

The detrimental impact of tobacco on human health is clearly recognized and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease (COPD) are susceptible to recurrent respiratory infections with pathogens, including non-typeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. As mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study to investigate chronic infection and the generation of adaptive immune responses to NTHI following chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-γ and IL-4, and B cells produced reduced levels of antibodies against outer membrane lipoprotein P6, with impaired IgG1, IgG2a and IgA class-switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke exposed mice exhibited a similar defect in the generation of adaptive immunity following immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes COPD patients to recurrent infections, leading to exacerbations and contributing to mortality.

Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD

“…In contrast there have also been reports of increased IgA in COPD lung tissue[12], but to date no study has comprehensively analysed immunoglobulin levels in the human airway in the context of NTHi infection, or in earlier stages of disease. Indeed the immune correlates of protection against this un-encapsulated organism are not fully understood, but murine models of COPD have demonstrated impaired immunoglobulin class switching in disease with associated effects on NTHi clearance[13]. Whether this is a relevant mechanism in man is not understood.…”

Influence of Time and Frequency of Passive Smoking Exposure on Mucociliary Clearance and the Autonomic Nervous System

“…These findings may be associated with the increased formation of free radicals when exposed to pollutants, starting an inflammatory reaction and releasing inflammatory cells and mediators (cytokines, chemokines, and adhesion molecules) that reach systemic circulation, leading to a subclinical inflammation, not only with repercussions in the respiratory system, but also causing systemic effects. 23,24 Thus, it is believed that with an increased exposure to load, there is a potentiation of these harmful effects. Thus, the reduction in pulmonary function may result in an increased risk of hospitalization, a prevalence of respiratory symptoms, and even death.…”

Randomized, double-blind, placebo-controlled superiority trial of the Yiqigubiao pill for the treatment of patients with chronic obstructive pulmonary disease at a stable stage

“…The levels of IL-8 have been observed to significantly increase in bronchoalveolar lavage fluid and sputum from patients with COPD (6,43). In the present study, it was determined that the decline in the percentage of CD8 + cells in peripheral blood and serum cytokine levels of IL-8 and TNF-α were reduced following intervention with the Yiqigubiao pill, as compared with the placebo.…”

“…The severity of COPD is impacted by airflow limitation progression, the chronic pulmonary inflammatory reactions to harmful airborne particles or gases, the occurrence of acute exacerbation (AE) COPD and complications. Recurrent acute exacerbations result in a decline in immunity, which then gradually leads to frequent and severe pulmonary infections (5,6).…”