**3. Conclusion**

and/or plasma from SCD patients during VOC [63]. Exposure to the plasma from SCD patients during VOC increased total NO production by both macro and microvascular lung ECs [63]. However, these increases were not accompanied by changes in eNOS or iNOS expression. Based on their findings, the authors suggested that altered NO production

The vascular inflammation and increased thrombotic activity known to occur in patients with ACS in SCD may be associated with platelet activation of ECs through CD40, a platelet associated pro-inflammatory molecule that promotes ECs activation and is known to be elevated in the circulation of SCD patients [69]. Cluster of differentiation (CD)40, a protein found on antigen-presenting cells and its ligand (L), a protein receptor, are members of the TNF superfamily of molecules. The binding of CD40 to the endothelial cell induces a variety of downstream effects and initiates a variety of immune and inflammatory responses including the production of reactive oxygen species (ROS), chemokines, and cytokines and the expression of adhesion molecules such as E-selectin, ICAM-1 and VCAM-1. The inflammatory response then fosters recruitment of leukocytes around the EC [69]. Furthermore, the ROS generated by CD40L antagonizes NO synthesis and additionally promotes EC dysfunction [69]. A cohort of SCD patients was evaluated for the association of CD40L and inflammation with SCD clinical complications including ACS [69]. It was found that plasma CD40L was associated with ACS and that SCD patients with a lifetime history of ACS presented with significantly higher plasma CD40L than in SCD patients that had never experienced an episode of ACS [70]. Thrombospondin (TSP-1), also a platelet derived protein that activates ECs was found in the same study to correlate with increased ACS ECs activation of

One of the factors that have been identified in ACS is increased adherence between sickled red blood cells (RBC) and ECs [71]. Some investigators interpret abnormal endothelial adhesion as evidence of a pro-inflammatory state [72]. The pro-inflammatory state in SCD is associated with endothelial damage, increased production of ROS, hemolysis, and increased production of pro-inflammatory cytokines [73]. Transgenic SCD mice have been used to study the inflammatory responses that occur in SCD in many organs including the lung. The transgenic mice models have an active inflammatory response similar to human SCD patients [74]. Adhesion molecules VCAM, ICAM and PECAM have been shown to be upregulated in LPS-treated normal and transgenic-treated lungs [74]. IL-6 and NF-kB expressions were also increased in the lungs of transgenic SCD mice suggesting a vigorous inflammatory response with activated macro and microvascular ECs in the lungs [74]. LPS challenge is associated with increased mortality and increased levels of serum and BALF cytokines TNF-α, IL-1β and VCAM-1 in

The role of the lung ECs and their interactions with sickle RBCs depend on multiple factors including the presence of inflammatory cells, cytokines, reactive oxygen species, hypoxic stress and infection that augment sickle cells' and white blood cells' (WBC) adherence to the endothelium. ACS is associated with infections, pneumonia, and fever, and in this setting, there is activation of pro-inflammatory factors such as cytokines that further activate the ECs and promote changes in vascular tone and permeability, anticoagulant-procoagulant balance,

might contribute to the pathogenesis of ACS [63].

298 Endothelial Dysfunction - Old Concepts and New Challenges

cytokines and chemokines [70].

sickle mice compared with control subjects [72].

and leukocyte trafficking in the lungs of the SCD patient [74].

Endothelial cells are an active component of the lung and line the large and small vessels of the lung. They all engage in forming a barrier separation but also are an active constituent in the healthy and diseased lungs. The pulmonary ECs manifest disruption and breakdown under abnormal conditions such as hypoxia and infection and pathologic conditions such as infection, ARDS, and ACS. The ongoing research in pulmonary ECs has highlighted the significance of pulmonary microvascular and macrovascular EC in health and disease with continuing focus toward improving morbidity and mortality of disease involving the pulmonary microvasculature.
