Lung - A Critical Immune Interface
Lungs are the most crucial organs for vertebrates to survive, via the intake of
oxygen from the air. Due to this continuous gaseous exchange with the air,
lungs are most vulnerable to infections by toxins, microbes, airborne pathogens,
or allergens. Based on the intensity and duration of exposure, lung infection can
vary from mild to acute. For example, COPD and allergic asthma trigger chronic
inflammatory responses in the lungs, whereas acute microbial infections cause
pneumonia or sepsis with severe inflammation to the lungs which can lead to
Acute Lung Injury / Inflammation(ALI) or Acute Respiratory Distress Syndrome (ARDS).
Being susceptible to such severe infections, lungs are designed to serve as a major
immune organ that can protect themselves autonomously from the microbes,
allergens, xenobiotics, or pathogens that enter our body through inhalation.
Although, lung epithelial cells are the principal targets of most respiratory viruses,
there is expanding evidence that lung epithelia themselves are capable of
generating antimicrobial responses. This immuneagainst pathogens can
also be enhanced by nasal adjuvant administration. Hence, lungs act as a
potent immunological interface that can generate local as well as
protective systemic immunity against external respiratory pathogens.
Major Immune Cells in Lungs
The figure below illustrates that lungs contain macrophages which may be
divided into alveolar macrophages and interstitial macrophages. Lungs also
contain alveolar and bronchial epithelial cells (AECs and BECs), Dendritic
cells, Natural Killer cells along with other Innate Lymphoid Cells
(ILCIS, ILC2s, and ILC3s), and adaptive immune cells like T and B cells to
protect them against pathogens, toxicants, and allergens inhaled.
Neutrophils also migrate to the lungs in response to infection or
inflammatory insult. These pulmonary innate immune cells release
several cytokines and, chemokines and serve as antigen presenting
cells (APCs) to regulate pulmonary innate as well as adaptive immunity.
Know the Genes Causing Respiratory Diseases
There are multiple genes that play a vital role in the initiation and progression
of lung diseases such as Tumor Necrosis Factor-a (TNFa), Transforming Growth
Factor-B1 (TGFB1), Glutathione S-transferases P1 and M1 (GSTP1, and GSTM1),
and superoxide dismutase 3 (SOD3). TLR3 and TLR5 trigger the progression of
severe respiratory diseases like pneumonia and chemokine ligand 2, Toll-like
receptor 4, T-helper cell 1 initiate tuberculosis. Researchers have further
identified a gene that is closely associated with nicotine addiction and lung
cancer. It has been seen that a specific region on chromosome 15 (15q25.1),
containing the nicotinic acetylcholine receptor subunit genes CHRNA3 and
CHRNA5 are responsible for the trigger point behind the lung carcinoma.
Pathogenesis of Respiratory Disease
Pathogenesis of major lung diseases depends on the type of infection and
the area of exposure and are discussed below
As we know, asthma is a type of chronic inflammatory airway disease
generally represented with the symptoms like - tightness in the chest,
wheezing, coughing, and dyspnea. All these symptoms are generally
associated with exacerbation of airway inflammation. Whatever be the
stimulus the symptoms often start with smooth muscle contraction and inflammation.
Although for a long time, researchers have found asthma is a reversible health
condition, recent research shows permanent structural changes in the airway
such as - sub-basement membrane fibrosis, smooth muscle hyperplasia, new
vessel formation, and glandular hyperplasia. All these changes are collectively
known as airway remodeling which is a significant part of asthma pathogenesis.
Research on persistent asthma pathogenesis showed that asthma airway
remodeling causes an accelerated decline in lung function, which may be
slower than COPD but its impact is permanent in bronchiolar airways.
Bronchial biopsies and induced sputum of COPD patients have revealed
the symptoms of lung inflammation. This inflammation appears to be
an enhanced or abnormal inflammatory response, which is beyond
the protective capacity of the lungs. It is suggested that the presence
of increased CD8+ T lymphocytes differentiates between smokers who
do and do not develop COPD. There's a correlation between T-cell numbers,
the quantity of alveolar destruction, and therefore the severity of airflow
limitation. However, smokers with normal lung function also show an
increased number of CD8* cells compared to non-smokers. There's a
significant decrease in T-lymphocyte infiltration in bronchial biopsy
specimens from subjects with severe COPD. Other cells like
macrophages, dendritic cells, epithelial cells, neutrophils play a
vital role in the pathogenesis
3. Chronic bronchitis
Inflammation of the central airways is a prominent feature in patients
with bronchitis. The pathogenesis of bronchitis involves an inflammatory
mononuclear cell infiltrate within the airway wall and a neutrophil influx
into the airway lumen. The molecular events that trigger inflammation in
mucus hypersecretion showed that chemotactic agents are derived not
only from tissue fluid but also generated by the infected bronchial
epithelium. For example - bronchial epithelial cells synthesize
interleukin (IL-8), a potent chemoattractant and activator of
neutrophils and lymphocytes. Airway inflammation often involves
the adhesion of infiltrating leukocytes to resident parenchymal cells
within the bronchi and to the extracellular matrix. The resultant
inflammation likely plays an immediate role within the clinical
features of the disorder.
Cells Involved in Pathogenesis
There are multiple cells that are involved in the pathogenesis of
1. Mast cells
The mast cells are one of the key players who trigger the early allergic
response within minutes of antigen exposure. The mast cell surface-bound
IgE is crosslinked by the antigen which leads to the activation of mast cells
and potent mediators such as - histamine, leukotrienes, prostaglandin D2,
thromboxane B2, and platelet-activating factors. These mediators result in
the contraction of airway smooth muscle, edema, and enhanced mucous
secretions which induce airflow limitation and generate acute asthma
symptoms. Mast cells also contribute to the persistence of airway
inflammation through cytokines (IFN-a, IL-1, IL-4, IL-5, IL-6, IL-8, IL-16) and
chemokines (MIP-1a, MIP-1b, MCP, and RANTES) secretions and occurrence
of latephase response.
The role of Eosinophils is closely connected to allergic diseases. They are
often presented within the airways of allergic asthmatics and correlate
with parameters of disease severity. These cells consist of potent mediators
in their granules such as major basic protein, eosinophil cationic protein,
eosinophil-derived neurotoxin, and eosinophil peroxidase. These proteins
can induce airway damage and contribute to airway hyperresponsiveness;
therefore, eosinophils have been proposed as principle effector cells in
asthma pathogenesis. additionally, these cells, which include leukotrienes,
cytokines, matrix metalloproteinase, and reactive oxygen species, have the
capacity of generating other important factors that could contribute to
airway obstruction and injury.
Recent studies that evaluated acute respiratory diseases (infectious also
as noninfectious) have revealed the presence of increased number of
neutrophils within the airway. These cells can presumably contribute to
the pathogenesis of asthma, COPD, or bronchitis through the assembly
of lipid mediators, reactive oxygen species, and proteases
(myeloperoxidase and matrix metalloproteinase.
Lymphocyte or T cells play an important role in the pathogenesis of asthma.
A T cell subset, Th2 type, secrete cytokines like IL-4, IL-5, IL-9, and IL-13.
These cells increase in number within the bronchoalveolar lavage fluid of
atopic asthmatics following the introduction of an allergen within the airway.
Through the generation of those cytokines, Th2 cells cause eosinophil activation,
IgE production, mucus, and the expression of adhesion molecules like VCAM-1.
The T cell is additionally capable of manufacturing numerousregulation of other
inflammatory cells and therefore the worsening of acute and chronic
Macrophages are often found predominantly within the lower airway and
represent almost 90% of cells recovered by bronchoalveolar lavage in normal
and stable asthmatic patients. These resident cells significantly contribute to
the normal host defense by phagocytosis, generation of enzymes, as well as
reactive oxygen species. They also enhance the inflammatory response of
cytokines like GranulocyteMacrophage colony stimulating factor (GM-CSF),
IL-1, IL-6, lipid mediators (LTB4, C4, D4, PGD2, and thromboxane A2), and
matrix metalloproteinase. Researchers have identified the significant ability
of macrophages to get anti-inflammatory cytokines like IL10, IL-12, and TGF-b.
A decrease in the production of those cytokines has been thought to trigger
the upregulated airway inflammation in asthma. Also, alveolar macrophages
can act as antigen-presenting cells within the airway.
6. Dendritic Cells
Dendritic cells are considered as professional' antigenpresenting cells within
the lung and have the potential to act against an antigen and present it to
T lymphocytes with subsequent development of a Th2 cell type which will
contribute to eosinophil maturation (through the generation of IL-5) and IgE
production (through the generation of IL-4).
Immune Modulation with Current Therapy
Over the past decade, there have been multiple trials of anti-inflammatory
agents in patients who were suffering from severe pneumonia, developed
sepsis, or systemic inflammatory response syndrome. The trials involved
inhibitors of TNF and endotoxin. Though the trials fail to establish a potent
therapy, it is now established that many of the cytokines, specifically TNF,
are essential for host defense against both intracellular and extracellular
pathogens. It gave a thought to the researchers that an infected organ would
need to send signals to the bone marrow for a continued supply of neutrophils,
for a sufficient host defense response.
On the basis of satisfactory preclinical data with G-CSF, clinical trials have
been initiated with the patients of community-acquired pneumonia,
multilobar pneumonia, and pneumonia with sepsis. A study suggested
that G-CSF can be regarded as an effective immunomodulator in a variety
of non-neutropenic patients such as hospital-acquired pneumonia or
immunosuppressed by alcohol.
A recent study identified that faster radiological resolution in patients
treated with G-CSF, accompanied with complications including adult
respiratory distress syndrome and disseminated intravascular coagulation,
G-CSF was well tolerated in a short trial of 18 patients with pneumonia and
severe sepsis. These favorable trends trigger further studies in multilobar
pneumonia and severe pneumonia with sepsis were initiated. Docke and
colleagues investigated IFN-y_in patients with immunoparalysis associated
with sepsis and revealed that downregulation of monocyte human
leukocyte antigen (HLA)-DR expression identifies a subgroup of septic
patients with a higher risk of hospital-acquired infection. Furthermore,
the investigators showed that IFN enhanced HLA-DR expression,
increased lipopolysaccharide-induced TNF responses, and improved
clinical parameters of sepsis in more than 80% of patients treated with IFN.
Immunostimulants in Respiratory Diseases
Recently, there have been several treatments to showcase the incidence of
ARTIS (Vitamin A, vitamin C, zinc, antibiotics). Among them, the trials with
immunostimulants (herbal extracts, bacterial extracts, synthetic compounds)
are very crucial which aim to enhance the immune defenses of the respiratory
tract. However, the data quality of most of the studies was below the
standard, insufficient, and too diverse to conclude.
Since chronic respiratory conditions remain global health threats, as
exemplified in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
pandemic. This manuscript explains that most of these chronic respiratory conditions
are marked by underlying chronic inflammatory processes. Therefore, immune
modulation has become a cornerstone for novel therapeutic options, shaping the
future of pulmonary medicine. It is important to explore immune modulation as a
promising option for future therapeutic interventions in respiratory diseases.