Pulmonary fibrotic diseases are characterized by proliferation of lung fibroblasts and myofibroblasts and excessive deposition of extracellular matrix proteins. In some forms of fibrosis, including idiopathic pulmonary fibrosis (IFP), progressive scarring of the lung can lead to respiratory failure and even death. Several subtypes of pulmonary fibrosis all classified under the umbrella term “interstitial lung disease” (ILD), that can be caused by various insults to the lung including chemical, immunological, physical and radiological, as well as genetic factors and susceptibilities. IPF is an irreversible, progressive disease with no known cause and is one of the most serious forms of lung fibrosis. Other common ILDs include chronic hypersensitivity pneumonitis (HP) and autoimmune connective tissue (CT)-ILD. Although the FDA has approved pirfenidone and nintedanib for IPF, these drugs only slow the progression of disease in some patients and have significant side effects. The global incidence of IPF is rising, with a mean survival time of 3-5 years after diagnosis that is shorter than that for lung cancer, highlighting an urgent need for more effective therapies (Jeganathan, Smith, & Sathananthan, 2021; Marshall, Salciccioli, Shea, & Akuthota, 2018). The FDA has granted orphan drug status to several upcoming IPF therapies entering clinical trials, but more options are urgently needed.

There is a great deal of attention being paid to the field of resolution of inflammation, and the families of bioactive lipids that promote resolution, termed specialized pro-resolving mediators, or SPMs. SPMs have proven to have potent anti-inflammatory and pro-resolving effects in many animal models of disease (reviewed in (Cagnina, Duvall, Nijmeh, & Levy, 2022; Chiang & Serhan, 2020)). They are exciting candidates for drug development; since they are endogenously produced, they are expected to be well tolerated, and they are easily derivatized to increase their selectivity, potency, and improve their pharmacokinetic properties. SPMs act through G protein coupled receptors (GPCRs), and GPCRs are the largest family of targets for drug development (Park, Langmead, & Riddy, 2020).

However, it is not immediately obvious if lung fibrosis or other fibrosing diseases should be candidates for SPM therapy. Some of the key effector cells in fibrosis are fibroblasts and myofibroblasts, and the involvement of classical inflammatory or immune processes is less clear. Here, we will review emerging evidence from cell culture, animal models and human patient samples that SPMs have therapeutic potential to treat IPF and other lung fibrosing diseases.