Phosphodiesterase-4 inhibitors dampen lung fibrosis during active tuberculosis: a preclinical study
Afsal Kolloli1, Ranjeet Kumar1 and Selvakumar Subbian1,*
1Public Health Research Institute center at the New Jersey Medical School, Rutgers University, 225 Warren Street, Newark, NJ. *Correspondence: firstname.lastname@example.org.
Background: Tuberculosis is a major killer among infectious diseases. Pulmonary fibrosis (PF) is a hallmark of cavitary tuberculosis (PTB), which remains even after antibiotic therapy. PTB patients with PF have compromised lung function and are more susceptible to secondary infections. Therefore, successful management of PTB should include efforts to improve the lung function of patients. Here, we tested the hypothesis that PF in PTB manifests as chronic inflammation in a rabbit model, which develops pulmonary cavitary disease similar to humans. We used an anti-inflammatory, phosphodiesterase-4 inhibitor (PDE4i) to validate our hypothesis in this model.
Methods: Rabbits were infected with Mycobacterium tuberculosis HN878 (Mtb) by aerosol exposure and treated for eight weeks with or without PDE4i, starting at four weeks post-infection. Masson's trichrome staining was performed to examine collagen deposition and fibrosis. Total RNA isolated from rabbit lungs was used for genome-wide transcriptome analysis and RT-PCR assays.
Results: In the lungs of non-treated, Mtb-infected rabbits, extensive fibrosis with significant collagen deposition was observed around the granulomas at 12 weeks post-infection. In contrast, the lungs of animals treated with PDE4i had reduced fibrosis and collagen deposition. Genome-wide transcriptome analysis of Mtb-infected rabbit lungs at 12 weeks post-infection showed upregulation of proinflammatory cytokines (TNFα and IL1β) and matrix metalloproteinases (MMPs) that are associated with PF. In contrast, the expression of genes involved in tissue remodeling, such as collagenase (MMP1), gelatinase (MMP2), elastase (MMP12) and membrane-type (MMP14) matrix metalloproteases and a matrix proteoglycan, decorin (DCN) was significantly downregulated (p£ 0.05) in the PDE4i-treated rabbit lungs.
Conclusion: Treatment with the PDE4i can substantially reduce the Mtb infection-induced PF in rabbits. This preclinical study suggests that PDE4i can be useful, as adjunctive therapeutic drugs, to improve PTB treatment's clinical outcome.