Smoker’s Macrophages
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Smoker's macrophages are
alveolar macrophage An alveolar macrophage, pulmonary macrophage, (or dust cell, or dust eater) is a type of macrophage, a phagocytosis#Professional phagocytic cells, professional phagocyte, found in the airways and at the level of the pulmonary alveolus, alveoli in ...
s whose characteristics, including appearance, cellularity,
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
s,
immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...
, and other functions, have been affected upon the exposure to
cigarette A cigarette is a narrow cylinder containing a combustible material, typically tobacco, that is rolled into Rolling paper, thin paper for smoking. The cigarette is ignited at one end, causing it to smolder; the resulting smoke is orally inhale ...
s. These altered immune cells are derived from several signaling pathways and are able to induce numerous
respiratory disease Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, ...
s. They are involved in
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
,
chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...
s (COPD),
pulmonary fibrosis Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory ...
, and
lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
. Smoker’s macrophages are observed in both firsthand and secondhand smokers, so anyone exposed to cigarette contents, or cigarette smoke extract (CSE), would be susceptible to these macrophages, thus in turns leading to future complications. Alveolar macrophages are crucial in processing inhaled substances including cigarette chemicals and
particulate matter Particulate matter (PM) or particulates are microscopic particles of solid or liquid matter suspended in the air. An ''aerosol'' is a mixture of particulates and air, as opposed to the particulate matter alone, though it is sometimes defin ...
. The chemicals in tobacco, such as
nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
,
tar Tar is a dark brown or black viscous liquid of hydrocarbons and free carbon, obtained from a wide variety of organic materials through destructive distillation. Tar can be produced from coal, wood, petroleum, or peat. "a dark brown or black b ...
, and
carbon monoxide Carbon monoxide (chemical formula CO) is a poisonous, flammable gas that is colorless, odorless, tasteless, and slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the si ...
, stimulate several physiological pathways, which influence the recruitment and functions of these macrophages. Some of the smoker’s macrophages are recruited from the circulating
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s while some are the original alveolar macrophages residing in the lung. The biochemical processes also lead to
immunomodulation Immunomodulation is modulation (regulatory adjustment) of the immune system. It has natural and human-induced forms, and thus the word can refer to the following: * Homeostasis in the immune system, whereby the system self-regulates to adjust immun ...
and dysregulated repair processes, so the malfunction of macrophages renders individuals more susceptible to infections. In addition, these inhaled substances can enter the bloodstream, especially nicotine which is rapidly transported to the brain, leading to addiction; it will subsequently distributed throughout the body, leading to carcinoma in the future. The morbidity of cigarette smoking is nearly 50% with 7 million first-hand smokers and 1.2 millions second hand smokers killed each year. Regardless of active or passive smokers, macrophage accumulation is found in the lungs. The diagnostic methods for smoke-related diseases include
bronchoalveolar lavage Bronchoalveolar lavage (BAL), also known as bronchoalveolar washing, is a diagnostic method of the lower respiratory system in which a bronchoscope is passed through the mouth or nose into an appropriate airway in the lungs, with a measured amou ...
which can also be used for examining smoker's macrophages in addition to augmented inflammatory cells in the alveolar lumen.


Appearance


Autofluorescence

The uptake of tar from cigarettes accumulates in alveolar macrophages and causes autofluorescence. The intensity of fluorescence, however, is independent of cigarette exposure. This indicates a maximum capacity of tar uptake; excess tar cannot be retained by macrophages. Another pigment in smoker’s macrophage is
hemosiderin Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderin Hemosiderin or haemosiderin is an iron-storage complex that is composed of partially digested ferritin and lysosomes. The breakdown of heme gives ri ...
which is involved in iron homoeostasis. Hemosiderin-laden pigmented macrophages are yellowish brown and found in the bronchiole and peribronchiolar alveolar space. The presence of these dirty macrophages has been a characteristic of many smoke-related lung diseases.


Physiological pathways mediating macrophage changes


Macrophage Polarization

A macrophage can be polarized into the classic M1 or M2 phenotype, and this phenomenon can be seen in cigarette consumption. In this polarization scheme, lower M1 markers and higher M2 markers have been observed. The reprogram of macrophage implies a dysregulated inflammation that can damage healthy lung cells. Macrophage polarization is mediated by three major signaling pathways:
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
,
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamm ...
, and JAK/STAT. Each signaling cascade can lead to different results depending on the length of smoke history. It is therefore important to evaluate the characteristics of research participants and specify the experimental conditions when examining smoker’s macrophages. It is anticipated that cigarette smoking inhibits signal transduction which alters gene expression and cytokine profile with increasing M2-like phenotype. This trait is involved in anti-inflammation and tissue repair, but this can also be pro-fibrotic. However, some studies found variation in the conventional polarization and found dual polarization in multiple diseases, yet the direction and extent of polarization are also different across diseases. Despite the contradiction, treatments targeting the polarization process have promising results.


NF-κB

In long-term smoking or established diseases, not only does CSE decrease the production of pro-inflammatory cytokines, but also impairs
TLR2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune sy ...
and
TLR4 Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approx ...
signaling. Its inhibitory effect on NF-κB also induces
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
of alveolar macrophage. Prolonged exposure to CSE hence leads to M2 polarization. Meanwhile, NF-κB pathways will be activated with low concentration of CSE or in previously unexposed individuals. The increased activity of NF-κB upregulates the production of pro-inflammatory cytokines
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
,
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
, and IL-8. The short-term exposure attracts macrophages and
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
s to the lung with a 4-fold increase in cellularity. Short duration also biases polarization towards M1 phenotype. The number of immune cells however will be normalized in 6 months, demonstrating the shift in signaling direction.


MAPK

Similar time and dose dependent effects of CSE are exerted on macrophage polarization through the MAPK signaling pathway which involves
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...
and ERK as intermediate signaling molecules. In diseased conditions due to long-term smoking, the inactivation of JNK reduces the levels of
reactive nitrogen species Reactive nitrogen species (RNS) are a family of antimicrobial molecules derived from nitric oxide (•NO) and superoxide (O2•−) produced via the enzymatic activity of inducible nitric oxide synthase 2 (Nitric oxide synthase 2A, NOS2) and NADPH ...
and pro-inflammatory cytokines with more M2-like phenotype. However, brief exposure to CSE triggers the activation of ERK that increases
MUC1 Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the ''MUC1'' gene in humans. Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its ...
, TNF-a, and IL-8 levels to produce inflammatory effects.


JAK/STAT

Cigarette contents also modulate multiple
STAT protein STAT, Stat., or stat may refer to: * stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, ...
s activities. In response to the smoking, STAT3 and STAT6 signaling are stimulated to potentiate M2-like phenotype with elevated IL-6, IL-10, IL-12, and TGF-b. In the meantime, the toxic nitrogenous chemicals and oxidative stress would be reduced. In post-smoke situations, reduction in STAT1 is associated with M1-like phenotype and the downregulation of
IFN-γ Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...
signaling.


Cholinergic Anti-inflammatory pathway

Nicotine in cigarettes modulates the above signaling pathways by binding to α-7 nicotinic receptors on macrophage or neurons, hence activating the
cholinergic anti-inflammatory pathway The cholinergic anti-inflammatory pathway regulates the innate immune response to injury, pathogens, and tissue ischemia. It is the efferent, or motor arm of the inflammatory reflex, the neural circuit that responds to and regulates the inflamma ...
. Changes can thus be directly mediated by binding of nicotine to macrophage or indirectly via the
Vagus nerve The vagus nerve, also known as the tenth cranial nerve (CN X), plays a crucial role in the autonomic nervous system, which is responsible for regulating involuntary functions within the human body. This nerve carries both sensory and motor fibe ...
. Upon binding, the inhibition of the NF-κB and activation of JAK2/STAT3 pathways lead to over-inhibition of pro-inflammatory cytokines and thus an imbalance toward anti-inflammatory cytokines. The result may be lethal if inflammation is not controlled.


Function abnormalities


Iron homeostasis

Cigarettes contain a small amount of iron, but cumulatively a larger quantity in daily smoking. The increasing iron exposure in the lung and airway affects both respiratory and systemic
iron homeostasis Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically impo ...
by modifying cellular response. Although direct etiologic link has not been established, there is a 4-fold increase in intracellular iron level and a concomitant iron release observed in smoker’s macrophage. While iron-loading affects macrophage activation and functions, excessive extracellular iron favors bacterial growth. Normally, activated alveolar macrophage secretes
lipocalin-2 Lipocalin-2 (LCN2), also known as oncogene 24p3 or neutrophil gelatinase-associated lipocalin (NGAL), is a protein that in humans is encoded by the ''LCN2'' gene. NGAL is involved in innate immunity by sequestering iron and preventing its use by ...
which traps bacterial
siderophore Siderophores (Greek: "iron carrier") are small, high-affinity iron- chelating compounds that are secreted by microorganisms such as bacteria and fungi. They help the organism accumulate iron. Although a widening range of siderophore functions is n ...
s and prevents bacterial iron uptake. Iron imbalance locally in the lung thus results in higher risk of infection. Hemosiderin is the iron storage in smoker's macrophage rather than
ferritin Ferritin is a universal intracellular and extracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. ...
. It is formed during hemorrhage or abnormal metabolism of ferritin. Indeed, buildup of iron causes oxidative stress resulting in lung damage and mitochondrial dysfunction. The level of hemosiderin-laden macrophage is also associated with pulmonary hemodynamics parameters which is used to evaluate pulmonary hypertension in the early stage of diseases. Iron homeostasis has been associated with macrophage polarization and reprogramming despite unclear causality in cigarette iron. M1 macrophage demonstrates high TF,
HAMP Hamp may refer to: People * Lionel Hampton (1908–2002), American jazz musician nicknamed "Hamp" * Hampton Hamp Pool (1915–2000), American football player * Elijah Hampton Hamp Tanner (1927–2004), American football player, head coach and sc ...
, and
FTH1 Ferritin heavy chain is a ferroxidase enzyme that in humans is encoded by the ''FTH1'' gene. FTH1 gene is located on chromosome 11, and its mutation causes Hemochromatosis type 5. Function This gene encodes the heavy subunit of ferritin, th ...
gene activities that mediates iron uptake. M2 macrophage on the other hand expresses FPN1 which causes iron release. Supplementing iron to mice predisposes macrophage to M2 phenotype and inhibits M1-mediated inflammation.


Immune Response

The immune functions in smoker’s macrophages are compromised, so the airway pathogens are more likely to accumulate and cause infection. Smoker’s macrophages have reduced expression of HLA-DR antigens, causing immunosuppression. In addition, nicotine impairs the phagocytosis of
M. tuberculosis ''Mycobacterium tuberculosis'' (M. tb), also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' ha ...
and also induces immunosuppression via the activation of alpha-7 nicotinic receptors. Meanwhile, due to the impaired TLR2 and TLR4 signaling, macrophages fail to recognize pathogens, so there is a decrease in pathogen clearance. Therefore, smokers are prone to acute respiratory tract infection and
community acquired pneumonia Community-acquired pneumonia (CAP) refers to pneumonia contracted by a person outside of the healthcare system. In contrast, hospital-acquired pneumonia (HAP) is seen in patients who are in a hospital or who have recently been hospitalized in the ...
.


Disease phenotype


Asthma

Asthma has been proven to have a causal relationship with smoking due to the modified inflammation reaction. Alveolar macrophages will be excessively recruited onto the airway wall, leading to a narrower airway for oxygen to pass through. Some patients may also be affected by airway remodeling. Smoker's macrophages affect the elastic fibers in the mucus layer of the airways, tightening the lumen and causing asthma. Symptoms of asthma include wheezing, coughing, and chest discomfort. To ameliorate the situation, drugs that either suppress the inflammatory response or relaxes the airway will be administrated, so air can pass through.


Chronic Obstructive Pulmonary Disease

Smoking is found to be the most important causative factor leading to COPD. Because of the altered inflammatory response of the macrophages, smoking induces inflammation across the entire airway, which in turns obstructs the airflow. Symptoms of COPD include persistent coughing, wheezing, chest infections and breathlessness. Treatments for COPD usually focus on the source of the problem, which is smoking, thus the general treatment is going through smoking rehabilitation which including
nicotine replacement therapy Nicotine replacement therapy (NRT) is a medically approved way to treat people with tobacco use disorder by taking nicotine through means other than tobacco. It is used to help with quitting smoking or stopping chewing tobacco. It increases th ...
, mental therapy for advice, and support to quit smoking. In certain urgent cases, direct constriction also occurs, in which
bronchodilator A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lun ...
s allow the airway to dilate.


Cancer

Tobacco smoking has been associated with cancer mainly along the respiratory tract, but may also lead to cancer in the bladder and renal pelvis. Upon smoking, carcinogenic chemicals are inhaled, affecting the inflammation response. As inflammation plays an important role in inducing cancer, with smoking affecting the inflammatory response of macrophages in the lungs, the dysregulated inflammatory response poses a higher risk in developing cancer along the airway. Symptoms of cancer mediated by cancer include lumps on the body, sudden weight loss, persistent coughing and tough swallowing. Treatments for cancer are generally surgery,
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
and
radiation therapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a therapy, treatment using ionizing radiation, generally provided as part of treatment of cancer, cancer therapy to either kill or control the growth of malignancy, malignant cell (biology), ...
. These treatments directly target the cancer cells to kill the cancer prior to smoking rehabilitation programs.


Prognosis

Smoking cessation Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is Addiction, addictive and can cause Substance dependence, dependence. As a resu ...
is one the most effective methods for managing numerous smoke-related diseases and other immune diseases such as
AIDs The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...
. It brings both short term and long term benefits as the mucus clearance is improved in 48 hours and the mortality risk of lung cancer is halved in 10 years. In addition, the immune system starts to recover in 15 days as the inhibitory effects of cigarettes on macrophages are removed. The risks of morbidity and mortality of infectious diseases are significantly reduced in 1 year and become comparable with non-smokers after 5 years of quitting. Meanwhile, the life expectancy after smoking cessation increased by 10 years with the reduced risks of these diseases. Furthermore, early cessation in the age of 25-34 enhances the survival rate at the age of 35 by 20-30% compared with an average smoker.


Future research

Cigarette smoking has been extensively researched to understand the mechanisms of how it affects the macrophages and causes diseases. Meanwhile, novel therapies are being developed to target the molecular pathways. Future treatments have higher specificity and can potentially reverse the changes to macrophage and the cytokine profile, hence improving the clinical outcomes of related diseases. In the meantime, governments around the globe are encouraging smoking cessation and some progress is made. However, the psychological challenge for smokers to commit to quitting is often omitted. For instance, smoking cessation has been associated with depression while individuals may also experience withdrawal symptoms. The psychological aspect of smoking could be further investigated to formulate a better rehabilitation strategy to aid smoking cessation.


References

{{Reflist Macrophages Respiratory physiology Health effects of tobacco