Recombinant human C5a-induced bronchoconstriction in the guinea-pig: A histamine independent mechanism

Regal, Jean F.; Fraser, Daniel G.

doi:10.1016/0952-0600(90)90036-i

Cited by 10 publications

(9 citation statements)

References 24 publications

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“…It is known that C5a induces the release of not only TNF-␣, but also a host of other inflammatory cytokines and various mediators that are reportedly also involved in IBD (22,23,53). Because the C5a antagonist used in our study is also known to prevent formation of a number of these mediators (21)(22)(23), this likely explains its greater efficacy over infliximab, which solely inhibits TNF-␣.…”

Section: Discussionmentioning

confidence: 76%

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Woodruff¹,

Arumugam²,

Shiels³

et al. 2003

The Journal of Immunology

109

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The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-d-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-α levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-α inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.

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Section: Discussionmentioning

confidence: 76%

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Woodruff¹,

Arumugam²,

Shiels³

et al. 2003

The Journal of Immunology

109

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“…Although the exact functions that C3a and C5a regulate in human lung disease require further examination, C3a and C5a have been shown to elicit functional responses in the lung. In guinea pigs, instillation of C3a or C5a into the lungs induces respiratory distress characterized by contraction of the smooth muscle in bronchioles and pulmonary arteries and recruitment of platelets and leukocytes in pulmonary vessels (51,52).…”

Section: Discussionmentioning

confidence: 99%

“…Instillation of the anaphylatoxins induces respiratory distress characterized by contraction of the smooth muscle walls in bronchioles and pulmonary arteries and aggregation of platelets and leukocytes in pulmonary vessels (51,52). Synthetic peptides, based on the carboxyl-terminal sequence of C3a, can also mimic these properties (53), and the addition of inhibitors to carboxypeptidase N potentiates the respiratory distress stimulated by instillation of C3a and C5a (54,55).…”

mentioning

confidence: 99%

Expression of the Complement Anaphylatoxin C3a and C5a Receptors on Bronchial Epithelial and Smooth Muscle Cells in Models of Sepsis and Asthma

Drouin¹,

Kildsgaard²,

Haviland³

et al. 2001

The Journal of Immunology

193

149

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The presence of the complement-derived anaphylatoxin peptides, C3a and C5a, in the lung can induce respiratory distress characterized by contraction of the smooth muscle walls in bronchioles and pulmonary arteries and aggregation of platelets and leukocytes in pulmonary vessels. C3a and C5a mediate these effects by binding to their specific receptors, C3aR and C5aR, respectively. The cells that express these receptors in the lung have not been thoroughly investigated, nor has their expression been examined during inflammation. Accordingly, C3aR and C5aR expression in normal human and murine lung was determined in this study by immunohistochemistry and in situ hybridization. In addition, the expression of these receptors was delineated in mice subjected to LPS- and OVA-induced models of inflammation. Under noninflamed conditions, C3aR and C5aR protein and mRNA were expressed by bronchial epithelial and smooth muscle cells of both human and mouse lung. C3aR expression increased significantly on both bronchial epithelial and smooth muscle cells in mice treated with LPS; however, in the OVA-challenged animals only the bronchial smooth muscle cells showed increased C3aR expression. C5aR expression also increased significantly on bronchial epithelial cells in mice treated with LPS, but was not elevated in either cell type in the OVA-challenged mice. These results demonstrate the expression of C3aR and C5aR by cells endogenous to the lung, and, given the participation of bronchial epithelial and smooth muscle cells in the pathology of diseases such as sepsis and asthma, the data suggest a role for these receptors during lung inflammation.

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“…Bronchoconstriction was not altered by pyrilamine despite an increase in plasma histamine levels. SQ 29,548, a selective thromboxane antagonist decreased the peak response only, while the superoxide dismutase and TXA2 inhibitor U-63557A altered the time course of the bronchoconstrictor response (39). The time course and magnitude of bronchoconstriction was not affected by selective depletion of PMN, platelets or both.…”

Section: Effects Of Complement Components C3a and C5a In The Guinea Pigmentioning

confidence: 82%

Rodent models of complement activation-related pseudoallergy: Inducers, symptoms, inhibitors and reaction mechanisms

Dézsi

Rosivall

Hamar

et al. 2015

European Journal of Nanomedicine

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Complement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction to intravenous administration of nanoparticle-containing medicines (nanomedicines). This review focuses on CARPA in rodent models: rats, mice, guinea pigs and rabbits. Information on all aspects of hypersensitivity reactions caused by known complement activators (zymosan, cobra venom factor) and different nanomedicines (liposomes, other drug carrier nanocarriers) in these species has been compiled and analyzed, trying to highlight the similarities and differences. What is most common in all species' reactions to i.v. complement activators, liposomes and other nanoparticles is a dose-dependent hemodynamic and cardiopulmonary disturbance manifested in acute, reversible rise or fall of blood pressure and respiratory distress that can lead to shock. Other symptoms include heart rate changes, leukopenia followed by leukocytosis, thrombocytopenia, hemoconcentration due to fluid extravasation (rise of hematocrit) and rise of plasma thromboxane B2. The results of a recent rat study are detailed, which show that rats are 2-3 orders of magnitude less sensitive to liposome-induced CARPA than pigs or hypersensitive humans. It is concluded that CARPA can be studied in rodent models, but they do not necessarily mimic the human reactions in terms of symptom spectrum and sensitivity.

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Recombinant human C5a-induced bronchoconstriction in the guinea-pig: A histamine independent mechanism

Cited by 10 publications

References 24 publications

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Expression of the Complement Anaphylatoxin C3a and C5a Receptors on Bronchial Epithelial and Smooth Muscle Cells in Models of Sepsis and Asthma

Rodent models of complement activation-related pseudoallergy: Inducers, symptoms, inhibitors and reaction mechanisms

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