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17.1 Introduction
Inflammatory disease (ID) is recognized as a leading cause of morbidity within the population and
its term comprises a comprehensive spectrum of diseases involved in chronic inflammation for the
progression of disease progression [1]. These conditions are linked to an engaged immune system,
encompassing activated immune cells and various biomolecules [2]. Inflammation serves as a
defensive response of an organism to counteract the intrusion of foreign entities such as viruses,
bacteria, and parasites [3]. IDs exert a profound impact on the physiology of organs, whether
deeply situated or superficially located. There are many conditions are present that affect various
organs, such as the intestine (inflammatory bowel disease; IBD), lungs (acute respiratory distress
syndrome; ARDS), liver (hepatitis), arteries (atherosclerosis), pancreas (pancreatitis), kidney
(nephritis), and heart (myocardial infarction). Similarly, psoriasis (influencing the skin), arthritis
(affecting joints), periodontitis (impacting dental health), and uveitis (affecting the eyes) are exam-
ples of IDs involving superficially located organs. It includes both “autoimmune diseases” and
“auto-IDs” [4]. The attack of the immune system on self-tissues like psoriasis, ulcerative, and rheu-
matoid arthritis is called an autoimmune disease in many diseases, whereas diseases like hepatitis,
uveitis, atherosclerosis, pulmonary diseases, myocardial infarction, pancreatitis, nephritis involves
uncontrolled inflammation called as auto-IDs [5]. In aggregate, IDs significantly contribute to the
global disease burden, commonly assessed through disability-adjusted life year (DALY) statistics.
For example, in 2017, the average DALY rate for both genders with chronic obstructive pulmonary
disease (COPD) was 1028.8 per 100,000 age-standardized years [6]. Over the decades, some small
molecules, like nonsteroidal anti-inflammatory drugs (NSAID), glucocorticoids, and antioxidants
have been widely used for the treatment of various ID, and other than their effect they have many
side effects like aseptic joint necrosis, gastrointestinal bleeding cardiovascular risk, liver/kidney
injury [7]. Certain monoclonal antibodies that target different pro-inflammatory cytokines,
chemokines, or other bio-macromolecules have been used in clinical settings or studied in preclini-
cal studies for the treatment of numerous conditions like rheumatoid arthritis (RA) [8], IBD [9],
17
Rational Design of Anti-inflammatory Therapeutics
Kratika Singh
1
, Anmol Gupta
2
, Irum Siddiqui
3
, Ashapurna Sinha
2
,
Mukesh Kumar Patwa
1
, and Urmila Singh
1
1
Department of Microbiology, King George Medical University, Lucknow, Uttar Pradesh, India
2
Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
3
IIRC-1, Department of Bioengineering, Integral University, Lucknow, Uttar Pradesh, India
390
atherosclerotic disease [10], and asthma [11]. These antibodies regulate molecular and cellular
procedures closely linked to inflammatory responses (IRs). Still, the clinical application of these
agents has been accompanied by various limitations and side effects like cost effectiveness, a pri-
mary or secondary lack of reaction, as well as an increased risk of serious infections [12].
Undesirable effects in large part result from the systemic delivery in nontarget cells and tissue,
irrespective of whether it’s small molecule drugs or biological therapies. In addition, for certain
newly developed therapies like specialized pro-resolving mediators, which exhibit potent
inflammation-resolving activity and are highly effective in treating the inflammatory disorder, it
also becomes challenging to provide a controlled release and site-specific distribution in inflamma-
tory cells/tissues [7]. Over the past decades, many cutting-edge drug delivery strategies have been
explored to overcome the drawbacks accompanying traditional formulations of anti-inflammatory
therapies.
17.2 Navigating Inflammation and its Microenvironment
Inflammation is a completely natural biological response to internal and/or external stimuli of a
biophysical or chemical nature. This reaction is distinguished by the coordinated involvement of
various inflammatory cells and molecular mediators. Based on the duration of inflammation, it is
possible to classify it into two types: chronic and acute inflammatory responses. Severe inflamma-
tion, which is characterized by the prominent clinical symptoms of redness, swelling, pain, and
heat, typically remains used for some hours to a few days. In response to invading tissue injuries,
acute inflammation is generally accompanied by a quick and remarkable accumulation of inflam-
matory cells (especially neutrophils), cytokines, fluid, and chemokines in the affected tissues/
organs [13, 14]. Acute IR typically resolves on its own, restoring tissue balance (Figure 17.1).
Nevertheless, should a pathological insult persist or resolution be unattainable, tissue injury and
an ongoing IR may occur, resulting in chronic inflammation that can endure for months or even
years. Monocytes/macrophages are likely to play a significant role in this process by releasing
numerous inflammatory cytokines, which are closely linked to the development of chronic dis-
eases. While the specific triggers and body responses determine the initiation and inflammation
progression, their shared physiological and pathological characteristics are important targets for
diagnosing and treating various inflammatory conditions. In the subsequent part, we will briefly
discuss the typical pathophysiological traits of the inflammatory microenvironment, which pro-
vide valuable insights for designing drug delivery systems and bio-responsive materials to manage
inflammation-related diseases.
17.2.1 Inflammatory Cell Infiltration and Vascular Permeability
The altered structure and function of the microvasculature are the most important characteris-
tics of initial inflammation. This results in the widening of blood vessels, reduced permeability
of the blood vessels, and an increase in white blood cells in the tissue [15]. Substances in the
plasma and cells that cause blood vessels to react, such as complement components, histamine,
serotonin, fibrin, kinins, prostaglandins, and platelet-activating factors, are unlikely to have the
main influence on the immediate responses. These substances can bind to specific receptors on
the cells that line the blood vessels, causing them to contract and form gaps. As a result, the per-
meability of the blood vessels increases, and fluids from the blood leak out within 30 minutes of
an injury.
391
Temporarily, the activation of cells that line the interior of blood vessels is initiated by these sub-
stances that induce inflammation to increase the synthesis of diverse molecules that promote cellular
adhesion. These molecules can be categorized into four primary groups, characterized by their func-
tion and structure: immunoglobulins, integrins, selectins, and cadherins. The cells lining the inner
walls of blood vessels display the expression of these molecules that promote adhesion. Subsequently,
these molecules aid the movement of white blood cells from the bloodstream into the damaged tis-
sues via a meticulously controlled process that encompasses various stages of attachment, rolling,
strong adhesion, and migration. The body’s IR involves diverse subgroups of white blood cells, such
as monocytes/macrophages, basophils, eosinophils, lymphocytes, and primarily neutrophils, as well
as mast cells. Neutrophils, which constitute a significant proportion of white blood cells in the blood-
stream (50–70%), play a significant role in the immediate response to inflammation. They perform a
number of tasks, including creating extracellular neutrophil traps, generating reactive oxygen species
(ROSs), and triggering and controlling the immune systems of the body [16, 17]. Monocytes can
migrate toward inflamed areas and transform into macrophages, which depends on the severity and
duration of the injury and different substance activations. These macrophages, along with invading
macrophages and their cytokines, are present in the tissues and play a crucial role in maintaining tis-
sue and host equilibrium during the acute phase response of inflammation.
Furthermore, peripheral acute inflammatory and immune reactions rarely lead to acute inflam-
mation in affected tissues, as short and controlled macrophage responses are linked to various
Initiation and filteration
Acute phase
Blood capillary
Endothelial cell
Migration
Tethring rolling
Phagocytosis
Digestion
Phagocytosis with
macrophage
scavanger receptor
and Ox-LDL
MMPs
TNF-alpha
ROS
ROS cathepsin
Firm adhesion
Diapedesis
Chronic phase
Figure 17.1 Inflammation and environment of inflammation with acute and chronic phases in connective
tissues.
392
noninfectious and infectious diseases [18]. Therefore, macrophages have been extensively
researched as potential targets for visualizing and treating various chronic inflammatory condi-
tions [19]. However, eosinophils, basophils, and mast cells are unlikely to play a significant role in
allergies, parasite-related inflammation, hypersensitivity, and asthma responses[20]. Consequently,
associated inflammatory conditions attack these cells. In addition to serving as therapeutic targets,
these unique inflammatory effector cells can absorb various substances and migrate to inflamma-
tory sites, making them interesting “Trojan Horses” for the targeted delivery of various molecules
and particulate therapies to inflammatory sites [20, 21].
17.2.2 Acidosis
Acidification occurs locally, which is associated with chronic and acute inflammations. In com-
parison to healthy tissues, the regions affected by inflammation generally display low-pH levels.
As an example, the pH in the area of cardiac ischemia ranges between 6.6 and 6.1 [22], whereas
levels ≥4.2 have been documented in the discontinuity microenvironment [23]. In the situation of
patients who have acute asthma, their inhaled vapor that condensed exhibited a pH of 5.2, in con-
trast to a pH of 7.8 in control individuals who were in good health [24]. Regular synovial fluid typi-
cally has a pH ranging from 7.4 to 7.8, whereas synovial fluid in arthritic joints decreases to a
range of 6.7–7.3 [25, 26]. The degree of the sickness and its inflammatory activity are related to
this pH drop. Consequently, this results in glycolysis that is independent of oxygen and an increase
in lactic acid production [27]. When the condensed breathed vapor from patients with acute
asthma cleared, it had a pH of 5.2 as opposed to 7.8 in healthy control individuals [28].
Consequently, this leads to glycolysis that is not dependent on oxygen and an increase in lactic
acid production [27].
During an infection, acidification in the spaces between cells can be contributed by bacterial
metabolites like lactate [29, 30]. Inflammatory lung diseases, including asthma and COPD, can
result in respiratory acidosis due to accidental inhalation of acids present in the air and pollution
from fog. Extended acid exposure can exacerbate acidosis due to varying airway pH controls,
which is a major risk factor for the development of bronchitis and asthma. By acting as warning
signs and regulating the production and release of extracellular acidosis, inflammatory mediators
alter the intrinsic properties of different immune and inflammatory cells [31, 32]. Furthermore,
delivery systems that display acid-triggered release behaviors for various medicines may be
designed using acidosis as an internal signal. It is important to note that, apart from these patho-
logical situations, various cells, organs, and tissues in the body have different levels of acidic envi-
ronments under regular physiological circumstances. For example, the gastrointestinal tract’s pH
gradient, which ranges from 5.6 to 7.6 in the colon to 1.1–3.6 in the stomach, is well-regulated [33].
To treat inflammatory disorders, a variety of pH-responsive biomaterials and delivery devices have
been created.
17.2.3 Increased Oxidative Stress in Tissues
ROS are chemical compounds that contain oxygen and display reactivity. Some examples of
typical ROS consist of hydrogen peroxide (H
2
O
2
), hypochlorous acid (HOCl), singlet oxygen
(
1
O
2
), hydroxyl radical (
•
OH), and superoxide anion radical (•O
2
−
). Physiological levels of ROS
play a significant role in the maintenance and regulation of cellular functions, like prolifera-
tion, survival, migration, and cell differentiation. Furthermore, ROS are important for the