Smoking and COVID: Effects on Lungs and Immunity

Smoking harms the lungs and weakens the immune system, increasing the risk of respiratory infections. When combined with COVID-19, which primarily targets the respiratory system, smoking can worsen disease severity and complicate recovery. Understanding how smoking impacts lung function and immune defense is crucial in assessing its role in COVID-19 outcomes.

Research has explored how smoking alters airway function, receptor expression, and inflammatory responses, all of which may influence susceptibility to infection. Examining these factors helps clarify why smokers face increased risks from COVID-19 and other respiratory illnesses.

Pulmonary Physiology In Smokers

Smoking causes structural and functional changes in the lungs, impairing gas exchange and weakening defenses against respiratory pathogens. Chronic exposure leads to airway inflammation, mucus hypersecretion, and alveolar destruction, compromising pulmonary function. The inhalation of toxic chemicals like carbon monoxide and formaldehyde triggers oxidative stress and disrupts the balance of proteases and antiproteases, accelerating elastin and collagen breakdown. This process leads to airway remodeling, a hallmark of chronic smoking.

One major consequence is reduced lung compliance due to emphysematous changes. Alveolar wall destruction enlarges air spaces, reducing surface area for gas exchange and making oxygen uptake less efficient. CT scans show that long-term smokers experience increased lung hyperinflation and air trapping, contributing to exertional dyspnea and reduced exercise tolerance. Pulmonary function tests (PFTs) often reveal a decline in forced expiratory volume in one second (FEV1), a key indicator of obstructive lung disease. Smokers experience a faster FEV1 decline than non-smokers, with some studies showing an annual reduction of 50–70 mL compared to 20–30 mL in non-smokers.

Cigarette smoke also disrupts mucociliary clearance, a primary respiratory defense. The cilia lining the airways become damaged, losing their coordinated movement, leading to mucus accumulation and increased bacterial colonization. In chronic bronchitis, persistent inflammation and excessive mucus production contribute to airflow obstruction. Histological analyses of smoker’s lung tissue reveal goblet cell hyperplasia and submucosal gland hypertrophy, which worsen airway narrowing and increase the risk of recurrent infections.

Nicotine Receptor Expression

Nicotine, the primary psychoactive component of tobacco smoke, binds to nicotinic acetylcholine receptors (nAChRs), a family of ligand-gated ion channels found in the nervous system and peripheral tissues, including the respiratory epithelium. These receptors, particularly α4β2 and α7 nAChRs, influence pulmonary physiology and airway responsiveness. Chronic nicotine exposure alters receptor expression, with increased α7 nAChRs in airway epithelial cells potentially affecting mucociliary clearance and epithelial barrier integrity.

In the lungs, nAChRs are expressed on bronchial epithelial cells, alveolar macrophages, and vascular endothelial cells, influencing mucus secretion, ciliary function, and vascular tone. Nicotine exposure increases α7 nAChR expression, which affects intracellular calcium signaling and airway remodeling. Changes in receptor expression influence cellular proliferation and differentiation in the bronchial epithelium.

Nicotine also affects airway smooth muscle reactivity. Experimental models suggest nicotine enhances airway hyperresponsiveness through α7 nAChR activation, increasing bronchoconstriction in response to irritants. This effect may be particularly significant in individuals with chronic obstructive pulmonary disease (COPD), where heightened airway sensitivity worsens airflow limitation. Nicotine’s impact on vascular endothelial cells promotes angiogenesis and increases vascular permeability, further complicating pulmonary function in long-term smokers.

ACE2 Receptor Modulation

Angiotensin-converting enzyme 2 (ACE2) serves as the primary entry point for SARS-CoV-2. This receptor is highly expressed in the lung epithelium, particularly on type II alveolar cells, where it regulates the renin-angiotensin system (RAS). ACE2 counterbalances angiotensin II by converting it into angiotensin-(1-7), a peptide with vasodilatory and anti-inflammatory properties that helps maintain pulmonary vascular homeostasis. However, smoking has been linked to altered ACE2 expression, raising questions about its impact on SARS-CoV-2 susceptibility and disease progression.

Research indicates that smoking leads to ACE2 upregulation in lung tissue. Transcriptomic analyses show increased ACE2 mRNA levels in smokers compared to non-smokers, suggesting prolonged tobacco use enhances viral entry receptor density in the respiratory tract. Heavier smoking is associated with greater ACE2 expression. In animal models, cigarette smoke exposure induces ACE2 upregulation alongside structural airway changes, reinforcing the idea that smoking modifies the cellular environment in ways that could influence viral infectivity.

The mechanisms behind this receptor modulation involve oxidative stress and epigenetic changes. Cigarette smoke contains reactive oxygen species (ROS) and other toxicants that induce DNA methylation changes, affecting gene expression. Oxidative stress triggers ACE2 upregulation through transcription factors like hypoxia-inducible factor-1α (HIF-1α), which is elevated in smokers. Experimental studies also suggest that nicotinic acetylcholine receptor activation may influence ACE2 expression patterns in lung tissue.

Immune And Inflammatory Responses In Smokers

Tobacco smoke creates chronic inflammation that disrupts immune regulation and weakens the body’s ability to fight infections. Inhaled toxic compounds trigger persistent inflammation in the respiratory tract, increasing the production of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). This inflammatory state disrupts immune signaling, impairing both innate and adaptive responses. Elevated cytokine levels contribute to airway damage and tissue remodeling, which can worsen respiratory infections, including those caused by SARS-CoV-2.

Smoking alters the function of key immune cells, including alveolar macrophages and neutrophils. Macrophages, the first line of defense against inhaled pathogens, exhibit reduced phagocytic activity in smokers, compromising their ability to clear viral particles and cellular debris. Neutrophils, meanwhile, become hyperactivated, releasing excessive proteolytic enzymes and reactive oxygen species (ROS) that contribute to lung injury. This paradoxical immune dysfunction—where some immune responses are suppressed while others are exaggerated—creates a dysregulated environment that can worsen COVID-19 outcomes.