Inflammation: A New Look at an Old Problem

Abstract

Pro-inflammatory stress is inherent in any cells that are subject to damage or threat of damage. It is defined by a number of universal components, including oxidative stress, cellular response to DNA damage, unfolded protein response to mitochondrial and endoplasmic reticulum stress, changes in autophagy, inflammasome formation, non-coding RNA response, formation of an inducible network of signaling pathways, and epigenetic changes. The presence of an inducible receptor and secretory phenotype in many cells is the cause of tissue pro-inflammatory stress. The key phenomenon determining the occurrence of a classical inflammatory focus is the microvascular inflammatory response (exudation, leukocyte migration to the alteration zone). This same reaction at the systemic level leads to the development of life-critical systemic inflammation. From this standpoint, we can characterize the common mechanisms of pathologies that differ in their clinical appearance. The division of inflammation into alternative variants has deep evolutionary roots. Evolutionary aspects of inflammation are also described in the review. The aim of the review is to provide theoretical arguments for the need for an up-to-date theory of the relationship between key human pathological processes based on the integrative role of the molecular mechanisms of cellular and tissue pro-inflammatory stress.

Keywords: atherosclerosis; cellular stress; evolution of inflammation; general pathological process; inflammation; neurodegeneration; systemic inflammation; tissue stress; tumors.

Figure 1

Variants of tissue pro-inflammatory stress. 1—Physiological variants of TS; 2—Non-classical low-grade inflammation (para-inflammation), which at systemic level may be manifest as stably altered homeostasis (allostasis); 3—Classical inflammation (the organism’s response to a significant local injury) is characterized by the presence of its attribute—a focus of inflammation and, in some cases, a systemic inflammatory response aimed at resourcing the focus of inflammation; 4—Life-critical systemic inflammation, the key phenomenon of which is a systemic microvascular response comparable in intensity to the local response in the focus of classical inflammation.

Figure 2

Tissue stress and general pathological processes (from Gusev E. et al., 2021). Note: The ratio of intensity to prevalence of damaging factors initiating a ‘response’ in the form of tissue pro-inflammatory stress—a common pathogenetic underpinning of all pathological processes—can be used to distinguish three ‘big’ general pathological processes (classical inflammation, systemic inflammation, and ChSLGI). The figure shows that the systemic manifestations of classical inflammation and ChSLGI may be comparable in terms of the localization and intensity of pro-inflammatory responses, requiring additional diagnostic methods to separate them.

Figure 3

Structure of typical cellular stress processes and its relationship with tissue stress.

Figure 4

Three stages of cellular stress development. Stage 1 is typical for proliferating cells; it is characterized by the predominance of growth factors in the secretory phenotype; relatively moderate manifestations of pro-inflammatory phenotype (including oxidative stress); dominance of anabolic processes; and adaptation to the moderate action of damaging factors. This stage can be complicated by the processes of tissue metaplasia and malignization. At the level of tissue stress, this stage is also typical for many physiological and pathology borderline processes, as well as for the repair (regenerative) stage of inflammation. Stage 2 is a transitional stage; it is characterized by different proportions between the first and third stages. Stage 3 is characterized by more pronounced manifestations of the pro-inflammatory phenotype in response to the increasing effect of damaging factors; increasing insulin resistance; cell cycle blockade; accelerated cell aging; an increasing role of autophagy and mitochondrial stress; and a high probability of programmed necrosis in the variant of pyroptosis, NETosis, and necrobiosis. When microvessels and migrating leukocytes are involved in these processes, conditions emerge for the formation of a canonical inflammation focus or for the development of systemic microcirculatory disorders as signs of systemic inflammation.

Figure 5

Organs with varying degrees of tissue stress under physiological conditions.

Figure 6

Pro-inflammatory tissue stress as a common basis for the development of general pathological and some physiological processes.

Figure 7

The main target organs in the development of chronic systemic low-grade inflammation.

Figure 8

Conceptual relationships between theoretical and clinical definitions.

Figure 9

A principal system for the relationships between tissue pro-inflammatory stress and key general pathological processes.