SerpinB3 Expression, PAR2 and SCCA-PD Polymorphism in Acute Respiratory Distress Syndrome

Respiratory Distress Syndrome (RDS), Respiratory Failure

ARDS, RESPIRATORY FAILURE, ICU

The Acute Respiratory Distress Syndrome (ARDS) is a systemic syndrome characterized by severe respiratory failure, inflammation, loss of aerated tissue and high mortality. Recently, significant efforts have been made to phenotype ARDS patients through a wide range of new biomarkers and imaging indices with the goal of developing personalized treatments based on patient's biophenotypization. Recent literature demonstrates, both in vitro and in vivo but not yet in ARDS patients, that the serine protease inhibitor(SERPIN)-B3 plays a crucial role in the pathological mechanism of pulmonary fibrogenesis, and, similarly, protease-activated receptors(PAR2) is highly involved in this aberrant inflammatory response. Consequently, studying the expression of SERPINB3 (including SCCA-PD polymorphism) and PAR2, in association with a detailed clinical and biomolecular phenotypization, could allow new insights into the pathophysiological mechanisms of lung injury during ARDS.

SERPINB3 is a strong activator of transforming growth factor-beta (TGF-b), an important pro-fibrogenic cytokine that also promotes epithelial-mesenchymal transition. Its expression can be induced/stimulated by oxidative stress. For example, in patients with idiopathic pulmonary fibrosis, the expression of SERPINB3 is significantly correlated with the presence of severe fibrosis and the expression of TGF-b. Recently, a new polymorphism of SERPINB3 (SCCA-PD) has been identified, featuring a single amino acid substitution in the reactive center loop of the protein, which enhances the functional anti-protease activity of this protein, inducing a more pronounced inflammatory and fibrotic response compared to wild-type SERPINB3, even in cultured monocytic cell lines. However, data is lacking in patients affected by ARDS. Furthermore, the reactive site loop of SERPINB3 has been shown to be essential for activating PAR2, another key element in the pro-fibrogenic cascade. PAR2 belongs to a subfamily of protease-activated G-protein-coupled receptors, consisting of four members, which plays a crucial role not only in activating the coagulation cascade and endothelendothelial inflammation but also in other stress-related clinical responses, such as pulmonary fibrosis. In conclusion, there is currently no data confirming a potential activation of the SERPINB3-PAR2 pathway in ARDS patient, which is presumably involved in the pathway of severe lung injuries affecting ARDS patients. More severe hyperinflammatory subphenotypes of ARDS are presumibely correlated with higher expression of SERPINB3, PAR2 and the presence of the SCCA-PD polymorphism. Thus, an early phenotypization of these critically ill patients could: i) allow the identification and characterization of a subgroup of patients at higher risk of pulmonary fibrosis and death; and, ii) promote the development of new therapeutic strategies, that counteract the fibroproliferative process during ARDS avoiding the activation of SERPINB3-PAR2 pathway, which could be a new pharmacological target for limiting the aberrant lung injury affecting ARDS patients (see 1-PPA). Demographic, clinical, and ventilatory data will be collected in accordance with our institutional protocols until hospital discharge. All patients will undergo a high-resolution chest CT scan within 72 hours of ARDS diagnosis using a multidetector CT scan to assess the fibroproliferative changes typical of pulmonary fibrosis. A second high-resolution CT scan will be performed 21 ± 7 days after ARDS diagnosis or at hospital discharge, whichever occurs first, to monitor the evolution of fibroproliferative pulmonary changes. Blood samples and BAL samples will be collected within 72 hours (and, only if available, at 21 ± 7 days) from ARDS diagnosis, as part of routine clinical practice. Only residual material will be used for research purposes.

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