Cigarette Smoke Particle-Induced Lung Injury and Iron Homeostasis

Abstract

It is proposed that the mechanistic basis for non-neoplastic lung injury with cigarette smoking is a disruption of iron homeostasis in cells after exposure to cigarette smoke particle (CSP). Following the complexation and sequestration of intracellular iron by CSP, the host response (eg, inflammation, mucus production, and fibrosis) attempts to reverse a functional metal deficiency. Clinical manifestations of this response can present as respiratory bronchiolitis, desquamative interstitial pneumonitis, pulmonary Langerhans' cell histiocytosis, asthma, pulmonary hypertension, chronic bronchitis, and pulmonary fibrosis. If the response is unsuccessful, the functional deficiency of iron progresses to irreversible cell death evident in emphysema and bronchiectasis. The subsequent clinical and pathological presentation is a continuum of lung injuries, which overlap and coexist with one another. Designating these non-neoplastic lung injuries after smoking as distinct disease processes fails to recognize shared relationships to each other and ultimately to CSP, as well as the common mechanistic pathway (ie, disruption of iron homeostasis).

Keywords: chronic bronchitis; ferritins; hypertension, pulmonary; iron; pulmonary disease, chronic obstructive; pulmonary emphysema; pulmonary fibrosis.

Figure 1

Schematic depicting the mechanistic basis for non-malignant lung injuries with smoking. CSP disrupts cell iron homeostasis by complexation and sequestration of intracellular metal. Host responses of inflammation, mucus production, and fibrosis attempt to reverse inadequate cell iron concentrations. Without correction, the deficiency in cell iron leads to irreversible cell death evident in emphysema and bronchiectasis. RB, respiratory bronchiolitis; DIP, desquamative interstitial pneumonitis; PLCH, pulmonary Langerhans’ cell histiocytosis; RBILD, respiratory bronchiolitis with interstitial lung disease; OP, organizing pneumonitis; NSIP, non-specific interstitial pneumonitis; UIP, usual interstitial pneumonitis.

Figure 2

Venn diagram of potential non-malignant lung injuries after cigarette smoking. Presentations with overlap between two or more lung injuries are numerous.

Figure 3

CSP in the human lung. Smokers show particle in close proximity to both airways (A) and vascular structures (B) and intracellularly within macrophages in distant sub-pleural regions (C). CSP is evident in lung resected from patients with inflammatory lung injury (D), fibrosis (E), and emphysema (F). Stain is hematoxylin and eosin. Magnification approximates 100×.

Figure 4

Siderophages in macrophages collected by bronchoalveolar lavage. Macrophages collected from nonsmoker (A) do not stain for iron (blue) while those from a smoker (B) do. Stain is Perls’ Prussian blue. Magnification approximates 400×.

Figure 5

Schematic for changes in iron homeostasis following CSP exposure. Functional groups at the surface of the CSP, including HULIS, complex and sequester iron from the cell. A functional metal deficiency results. In response to a reduction in intracellular iron, the cell upregulates iron import in an attempt to reacquire requisite metal. If the cell response to increase metal is inadequate, function and survival are compromised.

Figure 6

Schematic of iron import by polyanionic polysaccharide. Iron is bound by the polysaccharide using moieties such as carboxylates and hydroxyl groups. Lyase activity, increased by the metal deficiency, provides oligomers with bound iron to the cell for receptor-mediated uptake.

Figure 7

ECM components bind iron. Collagen demonstrates staining for iron (blue) supporting a role for uptake. The stain is colloidal iron. The magnification approximates 100×.

Figure 8

The correlation between CSP and emphysema. Lung tissue of a smoker exhibits a close association between CSP and emphysematous destruction of the parenchyma (ie, bullous formation). The magnification approximates 10x. Adapted with permission of the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights reserved. Ghio AJ, Hilborn ED, Stonehuerner JG, et al. Particulate matter in cigarette smoke alters iron homeostasis to produce a biological effect. Am J Respir Crit Care Med. 2008;178(11):1130–1138.