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  • Acute lung injury is present in sepsis and SIRS and

    2021-09-03

    Acute lung injury is present in sepsis and SIRS and is associated with increased pulmonary levels of proinflammatory cytokines and neutrophil extravasation into the alveolar space [19], [24]. Hauser et al. [25] observed that fragmented mitochondria induced pulmonary inflammation via neutrophil activation. Accordingly, we recently demonstrated that F-MITs was able to cause edema, neutrophil infiltration and alveolar septal thickening associated with increased myeloperoxidase activity [11]. Further, hemorrhagic shock caused lung damage via FPR and MAPK activation [11]. In the present study, we observed the presence of neutrophil elastase in lungs from Wistar rats that were intratracheally challenged with F-MITs. Conventionally, it is known that the function of neutrophil elastase is the killing and degradation of pathogens and dangerous molecules ‘captured’ by neutrophils, whereas the main target for extracellular elastase is elastin [25]. However, it has been shown that neutrophils, upon activation, release elastase and DNA to form an extracellular fibril matrix known as neutrophil extracellular traps (NETs) to immobilize and kill pathogens [18]. Several studies demonstrated that neutrophil elastase is increased in clinical and animal models of acute lung injury and instillation or systemic application of neutrophil elastase induces respiratory failure [26]. In line with these studies, we have observed that F-MITs induced neutrophils activation and elastase release in lung, likely via FPR activation, since non-formylated peptide (control) did not reproduce this result. Additionally, it was observed that F-MITs instillation induced an increase of iNOS protein expression in lung. iNOS is extensively distributed in different tissues including airways and lung and this isoform is induced by different molecules associated with inflammation, infection and injury, e.g. cytokines and microbial products. In addition, iNOS is involved in several diseases, including pulmonary hypertension and lasofoxifene sale [27]. Interestingly, it has been shown that lung inflammation after allergen challenge in mice is partially dependent on NO produced mainly by iNOS [27]. Also, iNOS activation increases lung chemokine expression to facilitate the influx of inflammatory cells into the airways [27]. In the present study, although we observed an increase in iNOS expression in airways and lung, its expression was coupled with neutrophil infiltration and activation in lung tissue. This result corroborates our previous work [11], where rats which underwent hemorrhagic shock presented with increased iNOS protein expression in lung via FPR activation. The FPR family has been most extensively investigated in the context of leukocyte recruitment and activation, where FPR promotes cell motility and mediates host defense [10], [12]. It is known that the bacterial N-formyl peptides are a potent chemoattractant [10], [12] with a high-affinity binding site for FPR. In an interesting study, Cardini et al. [28], reported that genetic ablation of the FPR1 gene (Fpr1) confers protection from smoking-induced lung emphysema in mice. Further, they observed that Fpr1 knockout mice displayed marked decreases in the lung migration of neutrophils and macrophages after cigarette smoke exposure [28]. Since FPR is expressed in airway segments [29] and its activation promotes cell motility, we questioned if F-MITs can bind to FPR and change airway contractility. We observed that F-MITs are able to induce contraction in a concentration-dependent manner in trachea, bronchi and bronchioles via FPR-2 activation in naive rats. Presently, the mechanism underlying selective activation of FPR2 by F-MITs in airway smooth muscle is unclear, however future studies will be performed to clarify this question. We also do not know how FPR-2 activation leads to contraction in airway segments. We can infer that FPR activation may induce actin polymerization leading to a slow contraction. This inference is based on our data showing that F-MITs instillation increased CDC42 protein expression in all airway segments evaluated. CDC42 is a member of Rho GTPase family, which regulates F-actin reorganization and induces actin polymerization, either by stimulating de novo actin nucleation or by stimulating the uncapping or severing of filaments [23]. Additionally, it is known that actin cytoskeletal remodeling is an important mechanism of airway smooth muscle contraction [30], therefore, in the present study we suggest that F-MITs bind FPR in airway segments leading to CDC42 activation and contraction. Supporting these data, it has been shown that FPR activation using bacterial N-formyl peptides significantly enhances epithelial cell restitution and migration via CDC42 [30]. Inhibition of Rac1 and CDC42 using pharmacological inhibitors and dominant negative mutants also inhibited the bacterial N-formyl peptides-induced increase in cell migration [30].