PARP1 and pulmonary disease
Fibrotic disease of the lungs idiopathic pulmonary interstitial fibrosis (IPF) is a result of enhanced fibroblasts proliferation and accumulation of collagen and extracellular matrix. This leads to alveolar injury, stiffening of airways, blood membrane thickening, chronic inflammation, damaged lungs and ultimately respiratory failure (Coultas et al., 1994; King et al., 2011). PARP1 enzyme is known to play critical role in many fibrotic disorders including heart (Gero et al., 2014), vessels (Abdallah et al., 2007), lungs (Genovese et al., 2005) and liver (Mukhopadhyay et al., 2014). Key observation of increased PARylation was reported in lung fibroblasts of IPF patients (Hu et al., 2013). PARP inhibitors are now reported to inhibit fibrosis and reduce collagen accumulation in liver. PARP1 inhibitor, HYDAMTIQ reduces the progression of bleomycin induced lung fibrosis by inhibiting the TGFβ/SMAD signalling pathway (Lucarini et al., 2017).
The characteristic feature of chronic obstructive pulmonary disorder (COPD) is airway inflammation, which could be due to reactive oxygen species (ROS) i.e. oxidative injury (MacNee, 2001). ROS induces PARP1 activation, although PARP role is to maintain genomic integrity, but excessive DNA damage could lead to PARP1 over-activation and finally cell death. One such study observed PARP1 activation in COPD via ROS and pharmacological inhibition of PARP1 or knockout has prevented epithelial cell injury and inflammation of airway (Boulares et al., 2003). It is interesting to note that oxidative stress, PARP1 and NFкB axis is connected to the inflammation observed in COPD, asthma and acute lung injury. Another study examined the requirement of PARP1 for induction of iNOS under oxidative stress during allergen induced eosinophilia (Naura et al., 2008). Allergen exposure may activate PARP1 that subsequently induces iNOS expression through NFкB. Moreover, PARP1 also regulates IL-5 production which in addition with other cytokines promotes eosinophil recruitment and promotes inflammation in lungs. iNOS reciprocally regulates PARP1 activity and thereby try to inhibit inflammatory response (Naura et al., 2008). Inhibition of PARP1 prevented the airway infiltration of eosinophils through IL-5 suppression (Oumouna et al., 2006). PARP1 is also known to modulate the Th2 cytokine (Oumouna et al., 2006) and ICAM-1 (Zerfaoui et al., 2009) expression in airways and hence regulates the eosinophil recruitment in lung airways. It has also been identified that PARP1 activation is a prerequisite for STAT6 expression which regulates the expression of IL-5 and GATA3 (Datta et al., 2011).
Preclinical analysis of PARP inhibition in dust mite exposed mice resulted in blocking asthma like traits. Furthermore, clinical analysis of the lung specimens and PBMCs derived from asthmatic patients presented activation of PARP1 in such patients (Ghonim et al., 2015). Moreover, PARP1 also contributes in epithelial-mesenchymal transition in airway remodelling in chronic asthma by formation of ternary complex through TGFβ and NFkB (Stanisavljevic et al., 2011). Thus, PARP1 has multifaceted role in lung diseases and hence could be a probable target for targeting symptomatic treatment in Covid-19 patients.