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The pulmonary microenvironment is truly unique as it is continuously exposed to insult through inhalation of pollution and microbes, tasking the pulmonary immune system with active maintenance of homeostasis. In the lung the resident immune cell is the alveolar macrophage. These cells, along with bone marrow derived infiltrating macrophages are capable of developing responses that can be characterized along a pro-inflammatory or pro-repair spectrum, which is dictated in part by the microenvironment. For example, resident alveolar macrophages are largely anti-inflammatory as the lung contains a number of immunosuppressive mechanisms to prevent activation. These macrophages surveil the lung and when necessary, mount an immune response to preserve lung function. Key to this inflammatory response in macrophages is inducible Nitric Oxide Synthase (iNOS) and iNOS derived nitric oxide (NO). NO can react with a large number of biological targets, the majority of which fall under three major categories: reactive oxygen and nitrogen species (RONS), metals and thiols. NO’s thiol based reactions serve as a signaling mechanism, forming S-nitrosothiols (SNOs) on proteins and small peptides. Formation of SNOs modifies the activity and function of a variety of proteins including enzymes and transcription factors, many of which have been implicated in macrophage activation and inflammatory signaling. Loss of NO has been found to alter the immune response in a model, and time dependent manner. Whether through genetic ablation or inhibition, loss of iNOS derived NO has been found to both reduce acute lung injury (ALI) in models of ozone, bleomycin, and LPS and worsen hyperoxia induced ALI, and bleomycin induced fibrosis. It is unclear which of NO’s bioactivity contributes to the previously observed effects, as well as the extent of NO’s thiol based signaling on regulation of macrophage activation. Using models of acute lung injury, fibrosis and adenocarcinoma the present studies confirm previous findings of model induced changes in macrophage activation, and then determine how increased SNO formation affected macrophage phenotype in these models. Using multiple methods of immunophenotyping, we observed that SNO formation limited pro-inflammatory macrophage activation in models of pulmonary inflammation. Additionally, consistent with microenvironment/macrophage crosstalk, these changes altered immune signaling in the lung microenvironment. In general, these changes in macrophage phenotype and immune signaling led to alterations in biomarkers of disease progression. Also observed were the effects of SNO signaling in multiple macrophage subsets, primarily observing differences in resident lung populations as opposed to those recruited to the lung, and alveolar space during inflammatory signaling. Our findings suggest that NO’s thiol based signaling present an opportunity to regulate inflammatory signaling and macrophage activation, as well as demonstrate the contribution of macrophage phenotype to the lung microenvironment.