Oxidative stress and poly(ADP-ribosyl)ation (PARylation) leads to tissue damage and inflammation in multiple lung diseases, likely in COVID-19. In a previous study we evidenced PARylation in multiple pulmonary cell types in patients who died of COVID-19, but not in patients who died of non-COVID-19 causes. We extended these observations in this retrospective immunohistochemical study by enlarging and stratifying the study population. We showed that pulmonary PARylation and oxidative stress peaked in the exudative and then decreased in the proliferative phase. Pulmonary oxidative stress and PARylation correlated with the serum markers of liver and kidney damage, oxygen transport, tissue hypoxia, lymphocytopenia, blood clotting and disseminated intravascular coagulation. Most correlations between PARylation and serum chemistry readouts were identified in the exudative phase. PARylation correlated with viral load and with the oxidative stress in the tissues, however, correlation between viral load and oxidative stress was marginal suggesting that oxidative stress and the presence of SARS-CoV-2 can independently induce PARylation. In males the time of hospitalization (time to death) was inversely correlated with pulmonary PARylation. Furthermore, males, died of COVID-19, were ∼15 years younger than females, however, there was no difference in pulmonary oxidative stress and PARylation between genders at death. Taken together, pulmonary PARylation and oxidative stress manifests early, in the exudative phase of COVID-19 and PARylation contributes to worse clinical outcome for males. These results suggest repurposing pharmacological PARP inhibitors for acute COVID-19 to counteract tissue damage.

The authors have declared no competing interest.

Our work is supported by grants from the NKFIH (K141142, FK146852, TKP2021-EGA-19, TKP2021-EGA-20) and the Hungarian Academy of Sciences (POST-COVID2021-33, NKM2022-30). Project no. TKP2021-EGA-19 and TKP2021-EGA-20 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary (NKFIH), financed under the TKP2021-EGA funding scheme. This project has received funding from the HUN-REN Hungarian Research Network. Supported by the University of Debrecen Program for Scientific Publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was authorized by the local ethical board of the University of Debrecen (6043/2022).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

↵* joint first authorship

Conflict of interest disclosure: The authors have no competing interest to disclose.