Prolonged Function of Macrophage, von Willebrand Factor-Deficient Porcine Pulmonary Xenografts

Cantu, E.; Balsara, Keki R.; Li, B.; Lau, Christine L.; Gibson, Sarah E.; Wyse, Ângela T. S.; Baig, Kamran; Gaca, Jeffrey G.; González-Stawinski, Gonzalo V.; Nichols, Timothy C.; Parker, William; Davis, Robert D.

doi:10.1111/j.1600-6143.2006.01603.x

Cited by 65 publications

(67 citation statements)

References 62 publications

(75 reference statements)

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“…[61,62] Alternatively, genetic knock out of von Willebrand factor prolonged survival of porcine pulmonary xenografts. [63] It was especially interesting that we identified several regulators that potentially transduce inhibitory signaling to control platelet activation or complement activation from previous report. However, these regulators have relatively poor sequence identity between Homo sapiens and Sus scrofa, and some even lack their homologues in Sus scrofa.…”

Section: Discussionmentioning

confidence: 94%

Sequence alignment analysis of proteins involved in platelet-endothelial cell interaction identifies molecular incompatibilities between Homo sapiens and Sus scrofa

Chen

Gao

et al. 2017

JBEI

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Background: Platelets play a vital role in acute humoral xenograft rejection (AHXR), presenting as microvascular thrombosis in the graft and/or consumptive coagulopathy in the recipient. Adhesion and aggregation of primate platelets to the activated vascular endothelial cells through sequential binding of ligands on endothelial cells and subendothelial matrix ultimately trigger a complex biological process of prothrombotic signaling cascades. Increasing evidence suggests that the molecular incompatibilities in effector molecules across species may partially contribute to dysregulated microvascular thrombosis in xenografts.Method: We selected amino acid sequence of candidate proteins from the NCBI database with keywords: platelet-endothelium interaction, platelet adhension, platelet aggregation, and subendothelial matrix ligands. Pair-wise amino acid alignments were made using the Emboss Needle method. Emboss needle created optimal global alignment of the amino acid sequences of human genes and pig genes using ClustalW2.Results: Most of the proteins involved in platelet-EC interaction in Homo sapiens share high sequence similarity with their homologues in Sus scrofa. Cytokines that potentially induce endothelial damage (such as CD40L, TNF-α) were highly conserved between Homo sapiens and Sus scrofa. Some endothelium-derived cytokines (such as IL-8, CCL2, CCL5) that can induce platelet activation or enhance aggregation share high sequence similarity between Homo sapiens and Sus scrofa. Some regulators that potentially transduce inhibitory signaling to control platelet activation or complement activation have relatively poor sequence identity between Homo sapiens and Sus scrofa, and some even lack their homologues in Sus scrofa.Conclusion: These characteristics of sequence similarity of proteins involved in platelet-EC interaction indicate the molecular incompatibilities between humans and pigs. This study provides clues for explanation of excessive platelet activity in pig-toprimate xenotransplantation model.

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Section: Discussionmentioning

confidence: 94%

Sequence alignment analysis of proteins involved in platelet-endothelial cell interaction identifies molecular incompatibilities between Homo sapiens and Sus scrofa

Chen

Gao

et al. 2017

JBEI

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“…They may be related to anatomical factors such as the fragile lung parenchyma-associated blood supply, as well as the presence of large numbers of inflammatory cells. The longest survival of a pig lung after transplantation in a non-human primate has been 5 days [58]. In contrast to the longer survival times of heart and kidney transplantations, lung transplantations are comparable with liver transplantation, which reached the longest survival of 9 days [57].…”

Section: Physiological Compatibilitymentioning

confidence: 99%

“…Barriers to successful lung transplantation appear to be even greater than for other organs [58]. They may be related to anatomical factors such as the fragile lung parenchyma-associated blood supply, as well as the presence of large numbers of inflammatory cells.…”

Section: Physiological Compatibilitymentioning

confidence: 99%

Recent Progress in Xenotransplantation, with Emphasis on Virological Safety

Denner

2016

Ann Transplant

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“…Using gadolinium chloride and clodronate liposomes, we and others have provided multiple lines of evidence to establish pro-inflammatory roles of PIMs in lung inflammation induced by bacteria, viruses, and endotoxin in many species such as cattle, horse, and sheep (29,35,44,49,53). It is worth noting that PIM depletion with gadolinium chloride reduced rejection of transplanted lungs in pigs along with reduced levels of thromboxane in pulmonary circulation to indicate PIMs as a major source of arachidonic acid metabolism (9). The depletion of induced PIMs in bile duct-ligated rats that are used as a model for hepato-pulmonary syndrome showed significant therapeutic effects such as reduced endotoxin-induced lung inflammation and mortality (18,55).…”

Section: Pims Influence Lung Physiologymentioning

confidence: 99%

“…The use of sheep, which have constitutive PIMs, as a model to study lung inflammation in humans that appear to lack constitutive PIMs raises a question as to the relevance of the data for humans (8). Similar questions may be raised regarding the use of pigs as a model to study lung transplantation in humans (9). The mechanisms of induction of PIMs in normal or inflamed lungs are yet to be investigated and understood in a meaningful manner.…”

mentioning

confidence: 99%

Pulmonary intravascular macrophages and lung health: What are we missing?

Schneberger

Aharonson-Raz

Singh

2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary intravascular macrophages (PIMs) are constitutively found in species such as cattle, horse, pig, sheep, goat, cats, and whales and can be induced in species such as rats, which normally lack them. It is believed that human lung lacks PIMs, but there are previous suggestions of their induction in patients suffering from liver dysfunction. Recent data show induction of PIMs in bile-duct ligated rats and humans suffering from hepato-pulmonary syndrome. Because constitutive and induced PIMs are pro-inflammatory in response to endotoxins and bacteria, there is a need to study their biology in inflammatory lung diseases such as sepsis, asthma, chronic obstructive pulmonary diseases, or hepato-pulmonary syndrome. We provide a review of PIM biology to make an argument for increased emphasis and better focus on the study of human PIMs to better understand their potential role in the pathophysiology and mechanisms of pulmonary diseases.constitutive pulmonary intravascular macrophages; induced pulmonary intravascular macrophages; human lung ONE OF THE STATEMENTS FROM a workshop on pulmonary immunobiology and inflammation sponsored by the National Heart, Lung, and Blood Institute in 1999 was, "In humans, the relative roles of endothelium, pulmonary intravascular macrophages, neutrophils, or other pulmonary cells in the clearance and processing of microorganisms and antigens from the systemic venous blood are poorly defined" (15). Since then, there has been significant advancement in understanding the roles of many of the indicated cells. However, the progress has been limited for the pulmonary intravascular macrophages (PIMs). We provide a focused review of the biology of PIMs to underscore a need to study their role in human lung disease.The role of vascular inflammation in regulating the organ and systemic inflammatory responses is well established. In this context, the contributions of intravascular mononuclear phagocytes such as hepatic Kupffer cells in microbial inflammation are well understood. In contrast, the PIMs are much lesser known and appreciated for their potential influence on lung physiology. PIMs range from 20 to 80 m in diameter and typically are firmly attached to the capillary endothelium on the thicker side of the alveolar septum, presumably to minimize the impact on gas exchange, in species such as cattle, horse, sheep, goat, and pigs (56, 64). PIMs' identity as macrophages in species such as cattle and horse was confirmed in situ through phenotyping with anti-macrophage antibodies (36,49). Although sheep lung is credited with the highest concentration of PIMs, which cover 20% of the capillary endothelium (56), the horse PIMs are the largest in size. The plasma membrane of PIMs exhibits a uniquely enhanced glycocalyx through decoration with lipid or lipoprotein globules of 50 -200 nm in size (Fig.

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Prolonged Function of Macrophage, von Willebrand Factor-Deficient Porcine Pulmonary Xenografts

Cited by 65 publications

References 62 publications

Sequence alignment analysis of proteins involved in platelet-endothelial cell interaction identifies molecular incompatibilities between Homo sapiens and Sus scrofa

Sequence alignment analysis of proteins involved in platelet-endothelial cell interaction identifies molecular incompatibilities between Homo sapiens and Sus scrofa

Recent Progress in Xenotransplantation, with Emphasis on Virological Safety

Pulmonary intravascular macrophages and lung health: What are we missing?

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