**4. Conclusions**

All the above mechanisms developed by microorganisms to avoid killing by NETs confirm

Netosis is a process being under control of many mechanisms of activation, but NET fibers seem not to be a target or location specific, and in some cases, their release get out of the control. So, the process can be a double‐edged sword, acting also against the host cells. Therefore, NETs seem to play a significant role in several autoimmune disease and disorders, described

A chronic inflammatory state of the lungs leads to the development of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) [121–123]. The increased permeability of alveoli due to a mechanical ventilation or infection causes an activation of signaling involved in the release of proinflammatory factors by epithelial cells, and in consequence the massive

NET release can be also the trigger of sterile inflammatory state in the lung. Moreover, a lack of surfactant proteins makes a NET clearance difficult. The proteolytic enzymes contained in NETs damage epithelial cells, in consequence releasing more proinflammatory factors. This

A similar mechanism was observed in patients with cystic fibrosis (CF), a disease consisting in an increase in mucus viscosity, therefore hindering the clearance of mucus from the airways [126]. The presence of DNA in CF patient sputum increases a mucus viscosity, which correlates with the development of inflammation state and higher migration of neutrophils. The high viscosity of mucus makes it difficult to remove, generating good conditions for bacterial invasion [126, 127].

Autoimmune diseases including small vessel vasculitis (SVV), systemic lupus erythematosus (SLE), or rheumatoid arthritis (RA) seem to be also associated with uncontrolled release and ineffective clearance of NETs [128–130]. The high amount of NETs and free‐circulating DNA causes a production of antineutrophil cytoplasmic antibodies (ANCAs) against DNA and NET‐associated proteins such as MPO, cathepsin G, elastase, etc. Autoantibodies to citrullinated proteins (ACPA) seem to be a key pathologic factor in RA. The circulating complexes of antibodies‐DNA or antibodies‐NET proteins induce multiorgan inflammatory states, as well

Deep vein thrombosis (DVT) is a next pathological state mediated by NETs. Neutrophils can be activated in veins by many different factors, including activated platelets, interleukins, proinflammatory cytokines, as well as von Willebrand factor (vWF), released by NET‐damaged endothelial cells. NETs, released inside veins, promote the formation of thrombi by binding

generates a self‐perpetuating mechanism of netosis activation [11, 124, 125].

their ongoing adaptation to the sophisticated processes of host defense.

**3.3. Role of nets in noninfectious diseases**

in detail in others reviews [54, 120].

14 Role of Neutrophils in Disease Pathogenesis

migration and activation of neutrophils.

*3.3.2. Autoimmune disorders*

*3.3.3. Thromvbosis*

as inflammations of vessels [11, 13, 131, 132].

*3.3.1. Lung diseases*

The progress in investigation of the fundamental processes leading to activation of netosis during pathogenic infection allows us to better understand the main causes of microbial infections and to consider the consequences of neutrophil responses to the host. All of them pointed out on the possible targets for novel therapeutic approaches regulating immunity responses during microbial infection and counteracting the detrimental NET formation and inflammatory diseases.
