Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), remains a devastating condition with a high mortality. It is characterised by alveolar injury and increased pulmonary vascular permeability. Vascular endothelial cell growth factor (VEGF) was identified by its properties to increase permeability and act as a cellular growth factor, hence its potential for a key role in the pathogenesis of ALI/ARDS. This review describes the basic biology of VEGF and its receptors as an essential prerequisite to discussing the available and sometimes paradoxical published data, before considering a paradigm for the role of VEGF in the human lung.

Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.

Rationale: Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-A₁₆₅a and VEGF-A₁₆₅b, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF. Objectives: To establish VEGF-A isoform expression and functional effects in IPF. Methods: We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTA^+/−TetoCre^+/−LoxP-VEGF-A^+/+ to conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice. Measurements and Main Results: IPF and normal lung fibroblasts differentially expressed and responded to VEGF-A₁₆₅a and VEGF-A₁₆₅b in terms of proliferation and matrix expression. Increased VEGF-A₁₆₅b was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-A₁₆₅b inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-A₁₆₅b to wild-type mice. Conclusions: These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-A_xxxa to VEGF-A_xxxb, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.

Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV₁ (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

Background: Non-cardiogenic pulmonary oedema is a characteristic feature of the acute respiratory distress syndrome (ARDS). The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in this condition. Lower VEGF plasma levels have been linked to the presence of the T allele in the +936 CT polymorphism. We hypothesised that the presence of the T allele would be associated with the development and severity of ARDS. Methods: A cohort of 137 normal subjects, 117 ventilated patients with ARDS, and 103 “at risk” of ARDS were genotyped for the VEGF+936 CT polymorphism. The severity of physiological disturbance and mortality was determined in the ventilated cohorts. Results: The CT and TT genotype frequencies were increased in ARDS patients compared with both normal subjects (OR 2.01, 95% CI 1.13 to 3.58, p = 0.02) and those “at risk” (OR 2.05, 95% CI 1.02 to 2.20, p = 0.03). In patients with ARDS but not those “at risk”, CT and TT genotypes were associated with a higher mean APACHE III score (80.9 (4.3) v 69.3 (2.9), p<0.05). Conclusion: These data support a role for VEGF in the pathogenesis of ARDS and its associated physiological derangement.