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.