Lung and general health effects of Toll-like receptor-4 (TLR4)-interacting SPA4 peptide

Abstract

Background: A surfactant protein-A-derived peptide, which we call SPA4 peptide (amino acids: GDFRYSDGTPVNYTNWYRGE), alleviates lung infection and inflammation. This study investigated the effects of intratracheally administered SPA4 peptide on systemic, lung, and health parameters in an outbred mouse strain, and in an intratracheal lipopolysaccharide (LPS) challenge model. Methods: The outbred CD-1 mice were intratracheally administered with incremental doses of SPA4 peptide (0.625-10 μg/g body weight) once every 24 h, for 3 days. Mice left untreated and those treated with vehicle were included as controls. Mice were euthanized after 24 h of last administration of SPA4 peptide. In order to assess the biological activity of SPA4 peptide, C57BL6 mice were intratracheally challenged with 5 μg LPS/g body weight and treated with 50 μg SPA4 peptide via intratracheal route 1 h post LPS-challenge. Mice were euthanized after 4 h of LPS challenge. Signs of sickness and body weights were regularly monitored. At the time of necropsy, blood and major organs were harvested. Blood gas and electrolytes, serum biochemical profiles and SPA4 peptide-specific immunoglobulin G (IgG) antibody levels, and common lung injury markers (levels of total protein, albumin, and lactate, lactate dehydrogenase activity, and lung wet/dry weight ratios) were determined. Lung, liver, spleen, kidney, heart, and intestine were examined histologically. Differences in measured parameters were analyzed among study groups by analysis of variance test. Results: The results demonstrated no signs of sickness or changes in body weight over 3 days of treatment with various doses of SPA4 peptide. It did not induce any major toxicity or IgG antibody response to SPA4 peptide. The SPA4 peptide treatment also did not affect blood gas, electrolytes, or serum biochemistry. There was no evidence of injury to the tissues and organs. However, the SPA4 peptide suppressed the LPS-induced lung inflammation. Conclusions: These findings provide an initial toxicity profile of SPA4 peptide. Intratracheal administration of escalating doses of SPA4 peptide does not induce any significant toxicity at tissue and organ levels. However, treatment with a dose of 50 μg SPA4 peptide, comparable to 2.5 μg/g body weight, alleviates LPS-induced lung inflammation.

The Role of Toll-like Receptors (TLRs) Mediated Inflammation in Pancreatic Cancer Pathophysiology

“…It has been shown that it can inhibit LPS-stimulated inflammatory responses, migration and invasion of colon cancer SW480 [ 157 ]. Similar results were also reported in the lung cancer [ 158 , 159 ].…”

Mechanism of Anti-Inflammatory Activity of TLR4-Interacting SPA4 Peptide

“…To understand the biological relevance of results from in vitro experiments, we included a mouse model of intratracheal E. coli LPS challenge that induces lung inflammation ( 30 ). Our previously published results demonstrated that the intratracheally administered SPA4 peptide on its own did not induce toxicity or inflammation but suppressed the LPS-induced lung inflammation, edema, and biochemical markers of tissue injury in mice ( 30 ).…”

“…To understand the biological relevance of results from in vitro experiments, we included a mouse model of intratracheal E. coli LPS challenge that induces lung inflammation ( 30 ). Our previously published results demonstrated that the intratracheally administered SPA4 peptide on its own did not induce toxicity or inflammation but suppressed the LPS-induced lung inflammation, edema, and biochemical markers of tissue injury in mice ( 30 ). As expected, the changes in BALF cell populations (increase in CD11b hi Gr1 hi , Gr1 + CD11b hi , Gr1 + CD11b med , CD11b + CD11c − , CD11b + CD11c + IAIE − CD14 − , CD11b + CD11c − IAIE lo CD14 lo-med , CD11b − CD11c + IAIE hi CD 14 lo-med , CD11b + CD68 lo F4/80 lo-med , and CD11b + CD14 − cell populations and a slight alteration in CD11b − CD11c − IAIE hi CD14 lo-med and IAIE + CD11c hi CD103 hi CD123 hi cell populations) were noted in LPS-challenged mice.…”

Revisiting the role of pulmonary surfactant in chronic inflammatory lung diseases and environmental exposure

“…Similarly, mice administered an SP-A-related peptide, SPA4, displayed a reduced inflammatory response following intratracheal LPS administration [127] as well as improved symptom and histological scores, increased bacterial clearance and reduced cytokine levels in mice infected with Pseudomonas aeruginosa [128].…”

“…Similarly, in both animal models [71,130] and in patients suffering acute asthma attacks [74,131], exogenous surfactant was associated with short-term improvements in lung function. There is also the potential of supplementing with collectins, as one research group has shown in several mouse models that administration of SPA4, an SP-A-related protein, was able to significantly improve the response to infection in a mouse model [127,128]. This highlights the importance of characterising the type, extent and cause of the surfactant dysfunction observed in a particular lung disease to best target the pathology.…”