Ism1, or Isthmin 1, is a secreted protein with diverse biological functions. It has been implicated in multiple pathways such as NODAL signaling, and is important in processes like organ development, metabolism, and immune response. Gene knockout (KO) mouse models have been crucial in elucidating its functions [4].

In KO mouse studies, Ism1 -/- mice showed intensified acute lung inflammation upon LPS challenge, with increased leukocyte infiltration and pro-inflammatory cytokine upregulation, and enhanced post-ALI lung fibrosis. This indicates Ism1's role in suppressing LPS-induced acute lung injury and post-injury lung fibrosis, likely through suppressing NF-κB activation [1]. Ism1 deficiency in mice also led to increased alveolar macrophage number and functional heterogeneity, causing chronic lung inflammation, emphysema, and lung function decline, similar to human COPD [2]. In renal development, Ism1 -/- mice had defective ureteric bud bifurcation and metanephric mesenchyme condensation, ultimately resulting in renal agenesis and hypoplasia/dysplasia due to compromised Gdnf/Ret signaling [3].

In conclusion, Ism1 plays essential roles in maintaining lung homeostasis, renal development, and metabolism. Gene knockout mouse models have been instrumental in revealing its functions in lung-related diseases like ALI, COPD, and in kidney development disorders. Its diverse functions suggest potential as a therapeutic target in these disease areas.