ABSTRACT
Background: The polymerized type I collagen (PTIC) is a g-irradiated mixture of pepsinized porcine type I collagen and polyvinylpyrrolidone (PVP). It has immunomodulatory properties. However, the receptor and signaling pathway through which it exerts its therapeutic effects has not yet been identified. Aim: To evaluate LAIR-1 as a potential receptor for PTIC and the signaling pathway evoked by ligand-receptor binding. Methods: LAIR-1 binding assay was performed by incubating various concentrations of recombinant human LAIR-1 with native type I collagen or PTIC. Macrophages M1-derived from THP-1 cells were cultured with 2-10% PTIC for 24 h. Cell lysates from THP-1, monocytes-like cells (MLCs), M1, M1+IFN-{gamma}, M1+LPS, and 2 or 10% PTIC treated M1 were analyzed by western blot for the transcription factors NF-{kappa}B (p65), p38, STAT-1, and pSTAT-1. Cytokines, Th1 cells, and M1/M2 macrophages were analyzed by luminometry and flow cytometry from blood samples of symptomatic COVID-19 outpatients on treatment with intramuscular administration of PTIC. Results: PTIC binds LAIR-1 with a similar affinity to native collagen. This binding decreases STAT-1 signaling IFN-{gamma}-induced and IL-1{beta} expression in M1 macrophages by down-regulating STAT-1 phosphorylation. Moreover, intramuscular PTIC treatment of symptomatic COVID-19 outpatients decreased at statistically significant levels the percentage of M1 macrophages and cytokines (IP-10, MIF, eotaxin, IL-8, IL-1RA, and M-CSF) associated with STAT-1 transcription factor and increased M2 macrophages and Th1 cells. The downregulation of inflammatory mediators was related to better oxygen saturation and decreased dyspnea, chest pain, cough, and chronic fatigue syndrome in the acute phase of infection and the long term. Conclusion: PTIC is an agonist of LAIR-1 and down-regulates STAT-1 phosphorylation. PTIC could be relevant for treating STAT-1-mediated inflammatory diseases, including COVID-19 and long COVID.
Subject(s)
Dyspnea , Chest Pain , Fatigue Syndrome, Chronic , COVID-19ABSTRACT
BACKGROUNDCurrently, therapeutic options for ambulatory COVID-19 patients are limited. OBJECTIVETo evaluate the safety, efficacy and effect of the intramuscular administration of polymerized type I collagen (PTIC) on hyperinflammation, oxygen saturation and symptom improvement in adult outpatients with symptomatic COVID-19. DESIGNDouble-blind, randomised, placebo-controlled clinical trial of PTIC vs placebo. SETTINGSingle Third-level hospital in Mexico City (Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran) PARTICIPANTSEighty-nine adult participants with a confirmed COVID-19 diagnosis and symptom onset within the 7 days preceding recruitment were included from August 31, 2020 to November 7, 2020 and followed for 12 weeks. Final date of follow-up was February 4, 2021. INTERVENTIONSPatients were randomly assigned to receive either 1.5 ml of PTIC intramuscularly every 12 h for 3 days and then every 24 h for 4 days (n=45), or matching placebo (n=44). MAIN OUTCOMES AND MEASURESThe primary outcome was a mean reduction of at least 50% in the level of IP-10 compared to baseline. The secondary outcomes were mean oxygen saturation [≥]92% while breathing ambient air and duration of symptoms. RESULTSOf 89 patients who were randomised, 87 (97.8%) were included in an intention-to-treat analysis; 37 (41.6%) were male and mean age was 48.5{+/-}14.0 years. The IP-10 levels decreased 75% in the PTIC group and 40% in the placebo group vs baseline. The comparison between treatment vs placebo was also statistically significant (P=0.0047). The IL-8 (44%, P=0.045), M-CSF (25%, P=0.041) and IL-1Ra (36%, P=0.05) levels were also decreased in the PTIC group vs baseline. Mean oxygen saturation [≥]92% was achieved by 40/44 (90%), 41/42 (98%) and 40/40 (100%) of participants that received PTIC at 8, 15 and 97 days of follow-up vs 29/43 (67%), 31/39 (80%) and 33/37 (89%) of patients treated with placebo (P=0.001). The unadjusted accelerated failure time model showed that patients treated with PTIC achieved the primary outcome 2.70-fold faster (P<0.0001) than placebo. In terms of risk, the group of patients treated with PTIC had a 63% lower risk of having a mean oxygen saturation <92% vs placebo (P<0.0001). Symptom duration in patients treated with PTIC was reduced by 6.1{+/-}3.2 days vs placebo. No differences in adverse effects were observed between the groups at 8, 15 and 97 days of follow-up. CONCLUSIONSIn this study, treatment with PTIC down-regulated IP-10, IL-8, M-CSF and IL-Ra levels, which could explain the PTIC effect on the higher proportion of patients with mean oxygen saturation readings [≥]92% and a shorter duration of symptoms as compared to patients treated with placebo. Although results are encouraging, larger randomised trials are needed. TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT04517162