Therapeutic potential of inhaled p38 mitogen-activated protein kinase inhibitors for inflammatory pulmonary diseases

Expert Opin Investig Drugs. 2008 Oct;17(10):1411-25. doi: 10.1517/13543784.17.10.1411.

Abstract

Background: Over the past two decades, p38 MAPK (mitogen-activated protein kinase) has been the subject of intense multidisciplinary research. p38 MAPK inhibitors have been shown to be efficacious in several disease models, including rheumatoid arthritis, psoriasis, Crohn's disease, and stroke. Recent studies support a role for p38 MAPK in the development, maintenance, and/or exacerbation of a number of pulmonary diseases, such as asthma, cystic fibrosis, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).

Objective: Many previous attempts to develop p38 MAPK inhibitors have failed as a result of unacceptable safety profiles. These toxicities have been varied and are believed to derive from different off-target effects.

Method: The above concerns can be overcome by delivering the compound locally to minimize whole-body burden, resulting in low exposure to the gastrointestinal, liver, and CNS. This review discusses the role of p38 MAPK in various inflammatory diseases, followed by the toxicity concerns associated with p38 MAPK inhibition. It also highlights the possible beneficial effect of delivering drugs via the inhalation route.

Conclusion: We present proof-of-principle confirming the therapeutic potential of inhaled p38 inhibitors for asthma and other inflammatory pulmonary diseases.

Publication types

  • Review

MeSH terms

  • Administration, Inhalation
  • Animals
  • Apoptosis
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / etiology
  • Asthma / drug therapy*
  • Cell Cycle
  • Cell Differentiation
  • Cell Movement
  • Humans
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pulmonary Disease, Chronic Obstructive / enzymology
  • Pulmonary Disease, Chronic Obstructive / etiology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • Protein Kinase Inhibitors
  • p38 Mitogen-Activated Protein Kinases