The State of the Nitric Oxide Cycle in Respiratory Tract Diseases

Abstract

This review describes the unique links of the functioning of the nitric oxide cycle in the respiratory tract in normal and pathological conditions. The concept of a nitric oxide cycle has been expanded to include the NO-synthase and NO-synthase-independent component of its synthesis and the accompanying redox cascades in varying degrees of reversible reactions. The role of non-NO-synthase cycle components has been shown. Detailed characteristics of substrates for the synthesis of nitric oxide (NO) in the human body, which can be nitrogen oxides, nitrite and nitrate anions, and organic nitrates, as well as nitrates and nitrites of food products, are given. The importance of the human microbiota in the nitric oxide cycle has been shown. The role of significant components of nitrite and nitrate reductase systems in the nitric oxide cycle and the mechanisms of their activation and deactivation (participation of enzymes, cofactors, homeostatic indicators, etc.) under various conditions have been determined. Consideration of these factors allows for a detailed understanding of the mechanisms underlying pathological conditions of the respiratory system and the targeting of therapeutic agents. The complexity of the NO cycle with multidirectional cascades could be best understood using dynamic modeling.

Scheme 1

O₂ complex with hemoglobin (Hb-O₂) and other heme proteins oxidize it to nitrate anion (NO₃⁻) (1); when interacting with superoxide (О₂⁻), toxic peroxynitrite (OONO⁻) is formed (2). In the absence of other reactive molecules, they are combined to form NO₃⁻ and CO₂. But in the presence of reacting molecules, for example, tyrosine, NO₃⁻ interacts with the resulting tyrosyl radical (tyr + CO₂⁻⟶tyr۰+CO₂) with the formation of nitrotyrosine (3 and 4). Small amounts of NO are reduced to N₂O. NO is oxidized to NO₂ dioxide, which gives higher oxides of nitrogen (N₂O₃ and N₂O₄) and many other reactions [8] (5). Thus, nitric oxide is able to interact with thiol groups (R-SH) and with iron-containing complexes, which play a leading role in the transportation and deposition of NO (6) [9].

Figure 1

Nitric oxide (NO) cycle. NO₂⁻: nitrite anion; NO₃⁻: nitrate anion; NO, N₂O₃, NO₂, and N₂O₄: nitric oxides I, II, III, and IV, respectively; RSH: thiols; RSNO: nitrosothiols; NO⁺: nitrosonium; OONO⁻: peroxynitrite; O₂⁻: superoxide anion radical.

Figure 2

Intertransformations of higher nitrogen oxides. N₂O, NO, N₂O₃, NO₂, and N₂O₄: nitric oxides I, II, III, IV, and V, respectively; k (1-16): reaction rate constants.

Scheme 2

Reduction of nitrates and nitrites in prokaryotes.

Figure 3

The action of globin proteins in the human nitrite reductase system. The figure shows the formation rate constants (k) of nitric oxide for various hemoproteins (Hb, Mb, and Ngb) of their nitrite anion. Neuroglobin has the highest rate of conversion of nitrite to nitric oxide (marked in red).