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  • A frequent complication of SIRS and sepsis is the developmen

    2022-01-14

    A frequent complication of SIRS and sepsis is the development of increased airway resistance and lung inflammation [2], [3]. For example, Uhlig et al. [3] demonstrated that rat lungs exposed to endotoxin present increased airway resistance due to constriction of terminal Deoxycorticosterone acetate [3] Moreover, it has been demonstrated that N-formyl-methionyl-leucyl-phenylalanine (FMLP), a bacterial chemotactic peptide, induces contraction of human airway [4] and lung inflammation in mice [5]. Therefore, during the onset of infection or sepsis it is clear that the presence of the pathogen is the primary cause of increased airway resistance and lung injury. However, the reason why patients that have sepsis-like symptoms or SIRS (sterile condition) also develop airway constriction and lung inflammation is still unknown. It has been proposed that cell components from traumatized tissue are the primary instigators of sterile inflammation or SIRS Deoxycorticosterone acetate [6], [7], [8]. These cell components are called damage-associated molecular patterns (DAMPs). DAMPs are endogenous molecules released from cells or tissues following injury, which activate the innate immune system in a similar manner to pathogens [7]. Mitochondrial N-formyl peptides are DAMPs that share similarities with bacterial N-formyl peptides. Although these peptides play a crucial role in the protein synthesis of bacteria and mitochondria [9], they are not used in cytosolic protein synthesis of eukaryotes. Therefore, mitochondrial and bacterial N-formyl peptides are recognized by the innate immune system as pathogens and are known to play a role in the initiation of inflammation by activating the formyl peptide receptor (FPR) [10], [11]. The FPR has been identified as a subfamily of G protein-coupled receptors [10]. It is well known that FPR-1 and FPR-2 are expressed at high levels on leukocytes, and that they mediate cell chemotaxis [10], [12]. More recently, it has been demonstrated that lung and tracheobronchial epithelial cells also express FPR and its expression is higher in response to scratch injury [13]. Interestingly, we were the first to observe that mitochondrial N-formyl peptides (F-MITs) are able to activate FPR in lung and cardiovascular system [6], [11]. This activation led to sepsis-like symptoms, including cardiovascular collapse and lung damage [11]. Based on these data, we hypothesized in the current investigation that F-MITs, which are released during traumatic injury, are able to induce airway contraction and lung inflammation. Therefore, if this hypothesis is correct, F-MITs may be an important instigator of airway dysfunction and respiratory failure observed in trauma-induced SIRS.
    Methods
    Results
    Discussion In normal conditions, fragments from mitochondria, including N-formylated peptides of mitochondrial origin, are supposed to be absent from plasma, given that mitochondria are located inside the cells. Also, this organelle, but not eukaryotic cells, uses N-formylmethionine to initiate all protein synthesis [9]. We observed that after cell trauma and injury in patients, these peptides are released into the circulation. However, only trauma patients that presented higher levels of F-MITs in the plasma demonstrated signs of SIRS and sepsis. Therefore, it is possible to infer that higher levels of F-MITs may be associated with the genesis and/or maintenance of systemic inflammation and multiple organ dysfunction, including respiratory failure, observed in patients with SIRS and sepsis. Since the worsening of lung function is correlated with the incidence of SIRS and sepsis [1], [19] in trauma patients, it is possible that F-MITs may be the molecular factor released after cell damage that leads to respiratory failure. Supporting these results, we previously observed that rats which underwent hemorrhagic shock presented lung injury and high levels of F-MITs into the circulation [11]. However, prior treatment with FPR antagonist decreased hemorrhagic shock-induced lung damage [11].