Acute Lung injury especially acute respiratory distress syndrome (ARDS) have been identified as life threatening conditions associated with significant mortality rate. Despite advances in the past decades in the knowledge on lung diseases, ARDS continues to claim the lives of more than 40% of its victims. The increase in health care associated costs has a major economic impact, while major clinical efforts to manage this disease are insufficient due to an uncomplete understanding of the mechanisms that control the pathology manifestations. Blood platelets, neutrophils and endothelial cells have been identified as the key components in the progression of ALI/ARDS. Moreover, our understanding of platelets function has shifted over the past years from a simple hemostatic tool to dynamic modulators of the immune response. The current paradigm of platelets intents to uncover the molecular mechanisms that make these cells major orchestrators of inflammation. Previous reports have demonstrated that the absence of platelets leads to increase endothelial damage, aberrant neutrophil function and hemorrhage during inflammation. Moreover, these effects have been shown to be controlled by the release of platelet granules during activation. To date, the identity of the platelet granule molecule or molecules involved in this remains to be elucidated representing gab in our knowledge. Accordingly, this study seeks to identify key platelet components that modulate systemic response during inflammation through the modulation of neutrophil-endothelial cell crosstalk and mechanisms involved. To dissect that question we will evaluate a platelet granule product known as TLT-1 in the mediation of the signaling mechanisms that modulates neutrophil -endothelial cell cross-talk during inflammation. The basis for the selection of TLT-1 as a potential target emerges from previous studies that demonstrated that TLT-1 knockout mice exhibited increased edema and hemorrhage together with a marked dysfunction of neutrophils during inflammation elicited by the Schwartzman reaction derived vasculitis. Moreover, we have evaluated TLT-1 functions in other models of inflammation including a mouse model of ALI using intranasal inoculation of LPS. Our preliminary data shows that TLT-1 prevents inflammatory associated hemorrhage while facilitate neutrophils transmigration in lung leading to decrease endothelial damage. Therefore, based on these previous observations we hypothesize that TLT-1 mediates the signaling mechanisms that regulate neutrophil capacity to transmigrate to the inflammatory site and modulate neutrophil- endothelial cell interactions during inflammation and therefore controlling the immune response. We developed two specific aims to answer that question.
The aims are as follows: (i) Define a role for TLT-1 in platelet-neutrophill-endothelial cell interactions during inflammation and (ii) Elucidate the therapeutic effects of TLT-1 on ALI/ARDS. This two aims will help to fulfill our current understanding of platelet biological functions in inflammation. The answers obtained through the realization of this research work will empower our knowledge to be able to develop new alternative treatments directed to control systemic response to inflammation.
Acute lung inflammation (ALI) and its characterized more severe form acute respiratory distress syndrome (ARDS) are life threatening diseases in very ill patients. These diseases are characterized by the presence of non-cardiogenic pulmonary edema and respiratory failure caused by an uncontrolled inflammatory reaction in the lungs. The development of targeted therapy against this deadly disease remains a great medical challenge, and clinical efforts are directed to reduce the mortality rate. A major hallmark of ALI/ARDS patients is reported to be platelet derived neutrophil dysfunction that lead to endothelial damage. The proposed dissection of the molecular mechanisms of AL/ARDS through the abundant platelet receptor known as Triggering receptor expressed on myeloid cells (TREM) like transcript 1 (TLT-1) is expected to significantly advance the current understanding of platelet modulation of immune response during inflammation while opening the door for new therapeutic approaches for this deadly disease.
|Morales-Ortíz, Jessica; Deal, Victoria; Reyes, Fiorella et al. (2018) Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model. Blood 132:2495-2505|
|Morales-Ortíz, Jessica; Rondina, Matthew T; Brown, Samuel M et al. (2018) High Levels of Soluble Triggering Receptor Expressed on Myeloid Cells-Like Transcript (TLT)-1 Are Associated With Acute Respiratory Distress Syndrome. Clin Appl Thromb Hemost 24:1122-1127|